**1. Introduction**

Cardiovascular disease (CVD) is one of the primary causes of death worldwide, with 22.2 million deaths expected by 2030. According to National Health and Nutrition Examination Survey (NHANES) data from 2013 to 2016, the prevalence of CVD was 48.0% in adults over the age of 20. The prevalence of CVD has a positive correlation with an increase with age [1]. The resulting social cost is estimated to have been 351.3 billion dollars in the U.S. alone, from 2014 to 2015. In particular, cardiovascular disease accounted for 14% of total medical spending in U.S., the highest rate among other major diagnostic groups—even higher than cancer. In the global population, the burden of expenditure is even more serious [1].

Providing sufficient information through image analysis acquired in the pre-operative diagnosis stage eliminates unnecessary examination and helps in developing patient-specific treatment plans.

As the heart is a continuously beating organ and there may be unexpected movements in patients (e.g., arrhythmia), if information on this movement can be obtained in advance, coronary artery and heart procedures may be more efficient.

As shown in Figure 1, the ECG signal is a change in potential that is correlated with the movement of the heart muscle. Motion of the heart produces changes in volume and pressure in the cardiac chambers; therefore, ECG provides important information about the movement of the heart. When CT is reconstructed by performing retrospective ECG synchronization, the movements of the heart and coronary arteries (according to the cardiac cycle) can be obtained geometrically, and movement information (e.g., coronary artery distortion), as well as characteristics of the coronary stenosis, can be obtained.

**Figure 1.** The ECG signal and volume of the ventricle during the different phases of a cardiac cycle.

Patient-specific 4D heart shape information facilitates the following applications: accurate coronary artery structure acquisition [2,3], analysis of 4D blood flow and stenosis [4–6], removal of motion artifacts in the vascular region [7–9], surgical simulation for each patient [10], postoperative evaluation and analysis [5,6], atrial motion analysis [11,12], vascular motion analysis [13,14], and real-time deformation prediction during surgery combined with 2D images [8].

In particular, cardiac CT angiography (CTA) has an isotropic spatial resolution of less than 0.5 mm and, so, can be used to observe the movement of the coronary artery and trabeculae of the ventricle. In addition to grading the degree of calcification of the coronary artery and the total amount of plaque from the CT image, it is also possible to measure the torsion of the coronary artery at a high resolution [15]. This high-resolution spatial information can help the operator perform a procedure appropriate for each patient before and after surgery. However, despite the high spatial resolution of the CTA, its temporal resolution is 50–200 ms, which is lower than that of 4D echocardiography (30–100 Hz) and cardiac MRI (30–50 ms). Therefore, proper shape interpolation for restoring high time resolution information from CTA imagery is essential for co-operation with the other applications while preserving high-precision anatomical details.

One of the essential requirements of cardiac modeling in many of these applications is that the topology of the mesh model constituting the cardiac model must be consistently preserved. In particular, in the case of a 4D heart model, the mesh should not cause new problems (e.g., self-intersection or mesh degeneration), even if the positions of the vertices constituting the shape change over time. To address these requirements, many researchers have employed the template-based registration scheme.

The registration process matches a template model to a target model through geometric shape deformation. The most popular registration algorithm is the iterative closest point (ICP) method, which consists of finding the correspondence between two models and finding the optimal transformation [16]. However, the ICP method is sensitive to the initial position and noise, while the shape registration is limited up to rigid transformation. Non-rigid registration deals with the deformation of the shape in addition to rigid transformations. Non-rigid registration is more challenging, however, as non-rigid transformations not only require more correspondences to be defined, but the solution space is much more extensive [17]. Research into the registration of 3D non-rigid shapes has been actively conducted using the methods of delineating shape deformation and shape correspondence.

To describe the deformation of an object, with respect to its dynamics and material properties, many researchers have assumed shape deformation to be a physical model, such as a linear elastic model [18], non-linear elastic model [19,20], viscous fluid [21], or diffusion model [22,23]. In particular, the Large Deformation Diffeomorphic Metric Mapping (LDDMM) framework provides robust deformation as a massive flow consisting of diffeomorphisms [24]. However, the physical models are computationally expensive and sensitive to mechanical properties. On the other hand, the statistical shape deformation model (SSM) uses a low-dimensional statistical model, in which shape deformation is inferred from a training data set [25,26]. Although SSM reduces the computational cost, the shape of variability is limited by the training data. Therefore, the deformation is hardly representative of the inter-variability of patients, such as the topological discontinuity of coronary arteries. Nora et al. described the motion modeling problem using the coronary arteries attached to the SSM of muscles [27]. Due to the representation of the coronary artery, the deformation poorly described the lumen diameter. Instead of modeling a priori physical and statistical information, there have been attempts to estimate the shape transformations with landmarks and coherent motions. Radial basis function methods express shape deformations as weighted sums of distance function for control point changes [28]. In particular, the thin-plate spline method minimizes the bending energy, which has a closed-form solution [29]. The most popular form of deformation is known as B-spline free-form deformation (FFD) [26,30,31]. Rueckert et al. [32] have proved the conditions for FFD to have diffeomorphic deformation. This method has disadvantages, however: the numerical cost increases with the number of control points and the degree of freedom of shape deformation is fixed. Therefore, the deformation has limited representation capacity.

In addition to deformation modeling, establishing correspondences between shapes is a critical problem in registration. The one-to-one correspondence of the ICP method is sensitive to the initial position and shape loss. To determine many-to-many correspondence points, Chui et al. [33] used the fuzzy correspondence between two shapes. The problem of selecting a robust point matching the correspondence has been interpreted as a combination of a Gaussian mixture model (GMM) and Expectation Maximization [34]. In the GMM model, one point is the centroid of the Gaussian distribution for the points constituting the shape, while the other point is regarded as the data to generate [35]. The variations of GMM have different deformation models, according to the obtained transformation parameters and the regularization term. For example, regularizing the second derivative of the transformation leads to a thin-plate spline transformation, while regularizing according to motion coherence theory leads to a coherent point drift transformation [36,37]. The variations of GMM have been generalized using the generalized Gaussian radial basis function [38]. To represent the local spatial representation, an *L*2*E* estimator has been proposed, which creates a robust sparse–dense correspondence [39,40].

However, the mixture model requires a high computational cost, as it generates a Gaussian distribution for each of the points. Furthermore, each Gaussian distribution shares its standard deviation among the points. The mixture model is thus sensitive to noise and shape loss. Especially for coronary arteries, narrow and tangled structures are very challenging to model in 3D+t. This is because the loss of blood vessel morphology can be observed in different heartbeats of the same patient, through motion artifacts and geometrical deformations.

In this paper, we propose a 3D+t coronary artery model that can be inferred in real-time, according to ECG signals. The overall structure of the proposed method is shown in Figure 2. The proposed patient-specific 3D+t coronary artery motion model is divided into two processing blocks, according to the timing of data processing; (1) a preoperative processing block, and (2) an intraoperative usage block.

**Figure 2.** General framework of the proposed method.

At the preprocessing step, we first perform the segmentation of 4D CTA volumes to generate artery models. After we have multiple coronary artery models, hierarchical cage-based registration is performed to construct a patient-specific 3D+t model with hyperelastic regularization. The proposed hierarchical cage deformation model more robustly/accurately registers coronary artery models in different cardiac phases. When updating the control points of the coronary artery model, we gradually increase the degrees of freedom of the deformation model. A modified hyper-elastic regularization term prevents mesh degeneration problems during the control point optimization step. After the optimal cage control point is obtained—which minimizes the shape dissimilarity of the source shape and the target shape—we interpolate the shape control point to build a continuous 3D+t model. The interpolated shape model provides fast shape-inference for intraoperative usage.

In the intraoperative usage step, the ECG phase can be assessed from the patient's real-time signal, which is then correlated to the geometric deformation of cardiac muscles, as shown in Figure 1. Therefore, the 3D shape of the coronary artery is provided by a continuous 3D+t model, according to change of the ECG signal and time.

The contributions of the proposed method consist of the following:


*Edited by Alessandro Rozim Zorzi and João Batista de Miranda*

This book presents a compilation of topics related to primary total knee arthroplasty. The chapters cover, in a clear and didactic way, the current themes, written by experts from the area, from different parts of the world.

Topics related to the three surgical phases (before surgery, during surgery, and after surgery) are discussed here. This is very important because the surgeon is not a "factory worker." First of all, it is a medicine doctor who has to feel and understand the particularities of each patient.

Demographic studies show an aging population. Osteoarthritis and inflammatory diseases are becoming much more prevalent. In addition, a worldwide epidemic of trauma has led to the need for arthroplasties much more frequently. Therefore, total knee arthroplasty will be an increasingly important subject.

Published in London, UK © 2018 IntechOpen © stockdevil / iStock

Primary Total Knee Arthroplasty

Primary Total Knee

Arthroplasty

*Edited by Alessandro Rozim Zorzi*

*and João Batista de Miranda*


**2.1. Optical materials**

Extensive research was involved in the elucidation of defects formation in glasses, as investi‐ gations were performed in glasses with various compositions under ionizing and non-ionizing radiation exposure. The studies were focused either on the materials degradation upon irradiation or on the possible use of such materials in radiation dosimetry [18, 19]. The radiation induced changes depend on the glass composition, total dose, dose rate, temperature and humidity during exposure, and post irradiation heating of the sample [19]. The operation of a glass-based dosimeter can be decided as function of radiation sensitivity, linearity of the response, stability of the radiation produced effect, and possibility to re-use the material.

Besides glass-based optical materials, radiation hardening tests were performed on various other optical materials. More than 20 years ago radiation induced defects were studied in BaF2 crystals by exposing them to gamma rays (from 10 Gy to 47 kGy) and observing the optical attenuation recovery (between 300 and 700 nm) under UV radiation and the scintillating signal [20]. Samples from different manufacturers exhibited radiation induced attenuation (RIA) saturation starting from 102 Gy. Crystal impurities and defects are the primary source of the optical attenuation increase in the 190–250 nm and 500–600 nm spectral bands induced by gamma rays [21]. BaF2 and LaF3 were subjected to Ne and U ions (at energies from 1.4 to 13.3 MeV/u) bombardment, and their degradation was investigated by scanning force microscopy (SFM), optical spectroscopy and surface profilometry. RIA for BaF2 shown an increase at λ = 240, 420, 550 and 750 nm, while LiF3 crystals remained almost unchanged spectrally. Surface topography studies indicated the presence of hillock in the irradiated zone [22].

Neutron irradiation was done on Y3Al5O12, CaF2 and LiF and RIA was monitored for UV-visible spectra. For Y3Al5O12 samples an increase of the optical attenuation was present for wavelength lower than 350–400 nm. CaF2 and LiF single crystals degrade their optical transmission after neutron exposure mostly in the 400–500 nm region. When heated after the irradiation RIA for the three crystals recovers according to different patterns [23].

by referring to radiation effects in optical materials and some photonic devices. According to this vision, the chapter is organized to cover the interaction of ionizing radiation with some optical materials and optical fibers, followed by a reference to radiation effects on some photonic devices based on optical fibers. The discussion addresses radiation effects produced by both energetic photons and charged particles, as appropriate [3]. In this context, an overview of some recently published results in the field is included, with a focus on original authors' contributions. The terrestrial radiation environments where optical and photonics components can be found include, but are not limited to, high energy physics experiments, nuclear power plants [3], fusion installations as the International Thermonuclear Experimental Reactor – ITER, or the Laser Mégajoule – LMJ [4–8], high power laser installations [9], nuclear waste repositories [10], high energy physics [11, 12], medical equipments for diagnostics or treatment [13]. On the other side, applications of optical components or photonic devices can be found in spaceborne instrumentation [14–16]. These environments involve various types of ionizing radiations, depending on the application considered: X-rays or gamma rays, electron beams, alpha

Extensive research was involved in the elucidation of defects formation in glasses, as investi‐ gations were performed in glasses with various compositions under ionizing and non-ionizing radiation exposure. The studies were focused either on the materials degradation upon irradiation or on the possible use of such materials in radiation dosimetry [18, 19]. The radiation induced changes depend on the glass composition, total dose, dose rate, temperature and humidity during exposure, and post irradiation heating of the sample [19]. The operation of a glass-based dosimeter can be decided as function of radiation sensitivity, linearity of the response, stability of the radiation produced effect, and possibility to re-use the material. Besides glass-based optical materials, radiation hardening tests were performed on various other optical materials. More than 20 years ago radiation induced defects were studied in BaF2 crystals by exposing them to gamma rays (from 10 Gy to 47 kGy) and observing the optical attenuation recovery (between 300 and 700 nm) under UV radiation and the scintillating signal [20]. Samples from different manufacturers exhibited radiation induced attenuation (RIA) saturation starting from 102 Gy. Crystal impurities and defects are the primary source of the optical attenuation increase in the 190–250 nm and 500–600 nm spectral bands induced by gamma rays [21]. BaF2 and LaF3 were subjected to Ne and U ions (at energies from 1.4 to 13.3 MeV/u) bombardment, and their degradation was investigated by scanning force microscopy (SFM), optical spectroscopy and surface profilometry. RIA for BaF2 shown an increase at λ = 240, 420, 550 and 750 nm, while LiF3 crystals remained almost unchanged spectrally. Surface

topography studies indicated the presence of hillock in the irradiated zone [22].

Neutron irradiation was done on Y3Al5O12, CaF2 and LiF and RIA was monitored for UV-visible spectra. For Y3Al5O12 samples an increase of the optical attenuation was present for wavelength

particles, neutrons, protons, and Bremsstrahlung [3, 14, 17].

**2. Radiation effects in optical materials**

**2.1. Optical materials**

38 Radiation Effects in Materials

Gamma irradiation (dose rate 110 Gy/h, total doses of 500 Gy, 2 kGy, 8 kGy, 20 kGy) was conducted on CaF2, Fused Silica and Clearceram in order to evaluate their qualification for space applications. RIA modification was measured over the 350–800 nm spectral interval at normal incidence. The optical investigations were completed by ellipsometry tests before and after the irradiation, from 200 nm to 1 μm. In the case of Clearceram, for example, three absorption bands located at 3.20, 2.20, and 1.81 eV are present. Over a quite long period these peaks decrease exponentially [24].

The scintillation properties of different optical materials were studied for their possible use in the development of radiation detectors. Two radiation induced luminescence (RIL) bands were observed in polycrystalline BaF2 irradiated by X-rays at 295 K, for the wavelengths intervals 380–600 nm and around 659 nm [25]. Under X-ray irradiation, ZnSe crystals present a degra‐ dation of the optical transmission at 475–575 nm, and four luminescence spectra at λ = 460 nm, 610 nm, 645 nm and 970 nm [26]. An X-ray induced RIL peak was reported in CaF2 crystals at λ = 420 nm, accompanied by a small one at about 350 nm [27].

Sapphire is one of the most intensively studied optical material under different ionizing radiation: X-ray (40 kV, 15 mA) and β from a 90Sr source at 1.5 Gy/min [28]; 8 MeV proton (flux 2 × 1012 p cm-2 s-1 and 150 MeV argon (4.3 × 108 ion cm−2 s−1) and 253 MeV krypton (4.3 × 108 ion cm−2 s−1) [29]; gamma rays (dose rate 6.7 Gy/s, total dose 108 Gy) combined with neutrons (energy 2.4 MeV and fluences of 1017–1020 n cm−2) [30]; fast neutrons (energy 1.2 MeV and fluence of 1.4 × 1018 n cm−2) [31], neutron irradiation followed by heating (energy 10 MeV, flux of 6.6 × 1012 n cm-2 s-1 and fluence up to 1019 n cm−2), maximum temperature 1000°C) [32]. Sapphire proved to be radiation hardened under gamma exposure up to high doses (108 Gy), but is more susceptible to optical transmission degradation under gamma-neutron irradiation as the optical attenuation increases with the fluence for wavelengths below 600 nm. RIL spectra change under gamma irradiation in relation to RIA modification [30]. For fast neutron irradiation, absorption bands develop at λ = 203, 255, 300, 357 and 450 nm, while post irradi‐ ation excitation produce photoluminescence signals at λ = 320, 377 and 551 nm [31]. High purity Al2O3 crystals present absorption peaks at λ = 206, 230, 258, 305, 358 and 452 nm, when irradiated by fast neutrons. Post irradiation annealing (up to 1000°C heating) contributes to partial recover of RIA. Excitation at λ = 302 nm induces luminescence at λ = 325, 482, 543 nm [32]. The RIL associated to the F- and F+ - bands was found to be dependent on the proton dose [29].

The invention of quantum cascade laser (QCL) [33] and subsequent research in the field made possible the development of compact, very accurate, and portable spectroscopic instruments for the mid-IR spectral range of interest for organic compounds identification (3–12 μm). Tunable QCLs or arrays of QCLs operating at different wavelengths proved to be affordable substitutes for Fourier transform IR (FTIR) systems to be used in astronomy, astrophysics, astrochemistry, and space missions [34, 35]. In order to operate reliably under extreme conditions as components to be included in spaceborne equipment, the composing parts of such equipment have to be tested under specific radiation exposure. Within this context, a program to evaluate for the Romanian Space Agency passive and active mid-IR components is under way. In this chapter, reference will be made to tests carried out on mid-IR windows materials (CaF2, BaF2, ZnSe, and sapphire—Al2O3). The subjects of these investigations are COTS (components-on-the-shelf) products, manufactured in Europe and China. The windows have 10–25 mm diameter and a thickness of 2–3 mm. Considering the complex space radiation environments which can be encountered during extra planetary missions, irradiation tests were run under various irradiation conditions: gamma rays (dose rate of 5.7 kGy/h +/–1.8%, four irradiation steps at total doses of 0.1 kGy; 1 kGy; 10 kGy; 20 kGy), alpha particles (doses from 1.46 × 106 kGy to 5.79 × 106 kGy, depending on the window material, at three beam currents of 100, 200 and 300 μC, beam diameter 3–4 mm), protons (at 1015 p cm−2, 1016 p cm−2, 1017 p cm −2 fluences), electron beam (dose rate of 4 kGy/min, total dose – several kGy). Gamma and electron beam irradiation were performed in air at room temperature, while proton and alpha particle irradiation were done in vacuum [36–38]. Prior and after each irradiation step the samples were measured in relation to their optical transmittance and reflectance over the spectral range from 250 nm to 18 *μ*m. **Figure 1** illustrates the setup for spectral reflectance evaluation, which was carried out with the Gooch and Housego OL Series 750 Automated Spectroradiometric Measurement System and the accessories (tungsten lamp and IR glower, diffracting gratings, integrating spheres, reflectance standards, optical detectors - Si & Ge, PbS, InSb and HgCdTe) appropriate to each spectral interval over which the measurements were done. Optical transmittance of the irradiated samples was used to assess the color centers generation (RIA) in mid-IR optical materials under various irradiation conditions (type of radiation, dose, and dose rate). In the mean time, during alpha particle irradiation the RIL was monitored on-line in order to associate this signal with the presence of some dopants/ impurities. The peak wavelengths of the detected radioluminescence are: λ = 285 nm (Caf2), λ = 405 nm (BaF2), λ = 465 nm (ZnSe), and λ = 700 nm (Al2O3). Significant decrease of the optical transmission was obtained for CaF2 and BaF2, below 1 μm, while a drop of the optical trans‐ mission over the investigated spectral range (0.3–16 μm) was noticed for all the materials except for sapphire, case when the transmission change was smaller as compared to other mid-IR materials. For the same purpose, RBS (Rutherford backscattering spectrometry) measure‐ ments were done on the investigated samples.

such equipment have to be tested under specific radiation exposure. Within this context, a program to evaluate for the Romanian Space Agency passive and active mid-IR components is under way. In this chapter, reference will be made to tests carried out on mid-IR windows materials (CaF2, BaF2, ZnSe, and sapphire—Al2O3). The subjects of these investigations are COTS (components-on-the-shelf) products, manufactured in Europe and China. The windows have 10–25 mm diameter and a thickness of 2–3 mm. Considering the complex space radiation environments which can be encountered during extra planetary missions, irradiation tests were run under various irradiation conditions: gamma rays (dose rate of 5.7 kGy/h +/–1.8%, four irradiation steps at total doses of 0.1 kGy; 1 kGy; 10 kGy; 20 kGy), alpha particles (doses

of 100, 200 and 300 μC, beam diameter 3–4 mm), protons (at 1015 p cm−2, 1016 p cm−2, 1017 p cm −2 fluences), electron beam (dose rate of 4 kGy/min, total dose – several kGy). Gamma and electron beam irradiation were performed in air at room temperature, while proton and alpha particle irradiation were done in vacuum [36–38]. Prior and after each irradiation step the samples were measured in relation to their optical transmittance and reflectance over the spectral range from 250 nm to 18 *μ*m. **Figure 1** illustrates the setup for spectral reflectance evaluation, which was carried out with the Gooch and Housego OL Series 750 Automated Spectroradiometric Measurement System and the accessories (tungsten lamp and IR glower, diffracting gratings, integrating spheres, reflectance standards, optical detectors - Si & Ge, PbS, InSb and HgCdTe) appropriate to each spectral interval over which the measurements were done. Optical transmittance of the irradiated samples was used to assess the color centers generation (RIA) in mid-IR optical materials under various irradiation conditions (type of radiation, dose, and dose rate). In the mean time, during alpha particle irradiation the RIL was monitored on-line in order to associate this signal with the presence of some dopants/ impurities. The peak wavelengths of the detected radioluminescence are: λ = 285 nm (Caf2), λ = 405 nm (BaF2), λ = 465 nm (ZnSe), and λ = 700 nm (Al2O3). Significant decrease of the optical transmission was obtained for CaF2 and BaF2, below 1 μm, while a drop of the optical trans‐ mission over the investigated spectral range (0.3–16 μm) was noticed for all the materials except for sapphire, case when the transmission change was smaller as compared to other mid-IR materials. For the same purpose, RBS (Rutherford backscattering spectrometry) measure‐

kGy, depending on the window material, at three beam currents

from 1.46 × 106

40 Radiation Effects in Materials

kGy to 5.79 × 106

ments were done on the investigated samples.

**Figure 1.** The sketch (a) and the picture (b) of the setup for spectral reflectance measurements over the UV to mid-IR (Reproduced with permission and courtesy of Gooch and Housego).

Spectral reflectance measurements were associated to optical microscopy tests as charged particles impinging on windows surface affect its quality (**Figure 2**).

**Figure 2.** The degradation of windows surface quality after alpha particle irradiation: (a) BaF2; (b) ZnSe (Courtesy of Laura Mihai).

For the first time, THz (Terahertz) spectroscopy and imaging were introduced (**Figure 3**) in the analysis of irradiated mid-IR optical materials.

**Figure 3.** 2D plot of the THz reflected signal for BaF2 window as the sample was scanned in the XY plane, for 0–2 THz (a); the frequency signal along the X axis (b), at a resolution of 50 μm (Courtesy of Laura Mihai).

### **2.2. Optical fibers**

Optical fibers were suggested to be possible candidates for radiation dosimetry through RIA, RIL or thermoluminescence monitoring [2]. Such applications were considered in the case of glass optical fibers and plastic optical fibers as well. The radiation induced effects depends strongly on the optical fiber composition of the irradiated optical fibers, a detailed discussion on radiation induced defects in Pure Silica Core (PSC) and doped optical fibers can be found in [39, 40].

Optical fibers based on different dopants were proposed for radiation dosimetry using the optical attenuation change under gamma irradiation: TiO2 and GeO2 + TiO2 in the silica core SM optical fibers [41]; Ge/Al co-doped SM fibers [42]; P2O5 doped step-index MM [43]. Depending on the experiment, low doses (dose rates of 0.01–1 Gy/h, for total doses up to 1 Gy) [43], moderate (dose rates 5–10 Gy/h, total doses of 10–100 Gy) [41] or high doses (dose rates of 2, 4 or 6 Gy/min, and the maximum total dose of 13 kGy) [42] were used. RIA was measured either at λ = 980, 1310 and 1530 nm [41, 42] or at λ = 502, 540 and 560 nm [43]. The recovery of the irradiation induced attenuation was studied at room temperature, through photobleaching (Ar laser radiation at λ = 514 nm) or by heating the samples (1000°C in O2 atmosphere at the pressure of 10 psi). Some of the studied samples (depending of the dopants concentration, wavelength considered, dose used, and radiation sensitivity) indicate a linear dependence of RIA with the dose, its independence with the dose rate and low recovery, which provide the ground for applications in radiation dosimetry.

For the first time, THz (Terahertz) spectroscopy and imaging were introduced (**Figure 3**) in

**Figure 3.** 2D plot of the THz reflected signal for BaF2 window as the sample was scanned in the XY plane, for 0–2 THz

Optical fibers were suggested to be possible candidates for radiation dosimetry through RIA, RIL or thermoluminescence monitoring [2]. Such applications were considered in the case of glass optical fibers and plastic optical fibers as well. The radiation induced effects depends strongly on the optical fiber composition of the irradiated optical fibers, a detailed discussion on radiation induced defects in Pure Silica Core (PSC) and doped optical fibers can be found

Optical fibers based on different dopants were proposed for radiation dosimetry using the optical attenuation change under gamma irradiation: TiO2 and GeO2 + TiO2 in the silica core SM optical fibers [41]; Ge/Al co-doped SM fibers [42]; P2O5 doped step-index MM [43]. Depending on the experiment, low doses (dose rates of 0.01–1 Gy/h, for total doses up to 1 Gy) [43], moderate (dose rates 5–10 Gy/h, total doses of 10–100 Gy) [41] or high doses (dose rates of 2, 4 or 6 Gy/min, and the maximum total dose of 13 kGy) [42] were used. RIA was measured

(a); the frequency signal along the X axis (b), at a resolution of 50 μm (Courtesy of Laura Mihai).

**2.2. Optical fibers**

in [39, 40].

the analysis of irradiated mid-IR optical materials.

42 Radiation Effects in Materials

Step index multimode, 16.0 mole% P2O5 co-doped (with and without 6.0 mole% GeO2 in the core) optical fibers were tested under gamma irradiation and shown a linear response at 505 nm for dose rates of 0.1 to 1 Gy/h, and a radiation sensitivity of 0.69–0.97 dB m−1 Gy, up to a maximum dose 1 Gy [44]. As the samples present an independence of the radiation response on the dose rate and a low recovery they seem to be suitable for medical dosimetry.

An investigation of gamma rays on polarization maintaining (PM) optical fibers to be used in interferometric fiber optic gyroscope (IFOG) for spaceborne assembles was carried out on three types of fibers: (i) pure-silica-core, (ii) P-doped (1 mol%), and germanium Ge-doped (15 mol %), as they were exposed to total doses of 100 Gy and 1 kGy. RIA was monitored over the spectral range 1100–1700 nm, with a focus on 1310 and 1550 nm. All the three fibers are more sensitive to radiation at 1550 nm than at 1310 nm, and the most degradation as it concerns RIA was observed in the case of the P-doped optical fiber [45].

On-line evaluation of gamma radiation produced RIA was investigated in 40 cm long Co/Fe co-doped alumino-silicate optical fibers fabricated by modified chemical vapor deposition (MCVD), and exposed to dose rates of 6.7, 18.4, 37.0, and 78.3 Gy/min, for 30 min to total doses of 201, 551, 1110, and 2348 Gy [46]. The measurements were done at 1310 nm with a Yokogawa AQ6370C optical spectrum analyzer. Following the irradiation, the attenuation in the doped fiber increases 258 times as compared to a reference optical fiber (SMF-28TM), and a small decay of the RIA signal was noticed after the irradiation ended. An almost linear relationship was present between RIA and the dose up to a total dose of 2.4 kGy at 78.3 Gy/min, which recom‐ mend this optical fiber for radiation dosimetry, as RIA dose rate independence was observed.

The performances of Ce-doped alumino-phospho-silicate optical fibers without Au (5.0 wt.% Al2O3, 0.15 wt.% P2O5, 0.3 wt.% CeO2) and with Au co-doping (5.1 wt.% Al2O3, 0.15 wt.% P2O5, 0.27 wt.% CeO2, and 0.2 wt.% Au2O3), produced by MCVD, were evaluated under electron beam irradiation at energy of ~6 MeV up to the total doses of 1012 e/cm2 , 5 × 1012 e/cm2 , 1013 e/ cm2 , 5 × 1013 e/cm2 , 1014 e/cm2 , and 2.5 × 1015 e/cm2 . RIA was monitored between 400 nm and 1100 nm, and post irradiation photobleaching under He-Ne laser radiation laser (λ = 543 nm) and UV. The results of the study indicated that the Ce/Au-doped optical fibers are more suitable for fiber-based dosimetry [47].

In the last years, the research focused also on the X-ray irradiation (10 keV energy) effects on various optical fibers: PSC, Ge-doped, P-doped, Fluorine-doped/ co-doped, in some cases the irradiation being combined with sample heating to 300°C [48, 49].

The irradiation outcomes in changing the optical fiber characteristics were investigated by online RIA measurements, confocal micro-luminescence (CML) and electron paramagnetic resonance (EPR), for total doses up to 3 MGy (dose rate of 50 Gy/s). RIA modifications in the UV-visible spectral range for Ge/F co-doped optical fibers produced under different conditions (draw speed and tension) were monitored with a mini optical fiber spectrometer (Ocean Optics HR4000) and deuterium-halogen DH2000 light source. Almost complete recovery of the irradiation induced attenuation was observed at room temperature for λ = 360 nm, corre‐ sponding to Ge(1) defects, at room temperature during the day following the exposure [49]. For various production conditions and different chemical composition the RIA vs. total irradiation dose graph indicates a linear dependency up to the dose of 300 kGy.

An interesting aspect in the research of optical fiber behaviour exposed to radiation is represented by the evaluation of radiation induced changes as heating is applied to the investigated sample. Different types of multimode UV optical fibers (deep UV enhanced, high OH step-index; solarization resistant, high OH step-index; UV enhanced extended spectral response, H2-loaded, step-index) were tested under gamma irradiation. In some circumstan‐ ces, the samples were heated to 573 K while irradiated, as the variation of the optical attenu‐ ation at specific wavelengths in the UV spectral range (*λ* = 248 nm, *λ* = 265 nm, *λ* = 320 nm and *λ* = 330 nm) was monitored. For some wavelengths (*λ* = 248 nm and *λ* = 265 nm) H2-loading improves radiation resistance, while heating during the irradiation of the same optical fiber increases their radiation sensitivity [50].

A complex research was carried out to evaluate the combined effect of radiation (1keV X-ray, 50 Gy/s dose rate and total dose from 1.5 KGy to 1 MGy) and heating up to 300°C, for different types of optical fibers [48]. The results of this investigation indicated that no unitary behavior with temperature during radiation exposure can be predicted in the case of PSC, Ge-doped, P-doped, Fluorine-doped optical fibers, as in some situations (fiber compositing, temperature range, total dose) the sample heating has no effect in compensating the defects generation, while in some others RIA increases or decreases with the temperature increase. In any case, some of the study conclusions refer (i) to the possible use of such fibers in radiation dosimetry, especially at low doses, and (ii) to the limited length of fiber which can be incorporated into distributed radiation sensing systems.

A recent contribution to the use of optical fibers in radiation dosimetry refers to some studies carried out in cooperation with a team working at the European Synchrotron Radiation Facility, in Grenoble on UV multimode optical fibers subjected to synchrotron radiation [51]. In this experiment were tested five types of commercially available UV optical fibers and offline measurements concerning the degradation of the optical fibers transmission in the UVvisible spectral range were done, as color centers developed upon exposure to synchrotron radiation. The measurements were performed for different doses: 5, 10, 30, 60, 200, 400, 1000 and 2000 Gy. The radiation induced optical attenuation was monitored in relation to recovery phenomenon both at room temperature and after samples heating to 560 K. The change of optical transmission and the increase of the attenuation at specific wavelengths (λ = 215 nm; λ = 229 nm; λ = 248 nm; λ = 265 nm; λ = 330 nm) were performed using the setup presented in **Figure 4**. The measurements were done with a dedicated software control developed under LabVIEW, by using a broadband UV-visible light source, a sensitive optical fiber spectrometer, and an optical fiber multiplexer.

resonance (EPR), for total doses up to 3 MGy (dose rate of 50 Gy/s). RIA modifications in the UV-visible spectral range for Ge/F co-doped optical fibers produced under different conditions (draw speed and tension) were monitored with a mini optical fiber spectrometer (Ocean Optics HR4000) and deuterium-halogen DH2000 light source. Almost complete recovery of the irradiation induced attenuation was observed at room temperature for λ = 360 nm, corre‐ sponding to Ge(1) defects, at room temperature during the day following the exposure [49]. For various production conditions and different chemical composition the RIA vs. total

An interesting aspect in the research of optical fiber behaviour exposed to radiation is represented by the evaluation of radiation induced changes as heating is applied to the investigated sample. Different types of multimode UV optical fibers (deep UV enhanced, high OH step-index; solarization resistant, high OH step-index; UV enhanced extended spectral response, H2-loaded, step-index) were tested under gamma irradiation. In some circumstan‐ ces, the samples were heated to 573 K while irradiated, as the variation of the optical attenu‐ ation at specific wavelengths in the UV spectral range (*λ* = 248 nm, *λ* = 265 nm, *λ* = 320 nm and *λ* = 330 nm) was monitored. For some wavelengths (*λ* = 248 nm and *λ* = 265 nm) H2-loading improves radiation resistance, while heating during the irradiation of the same optical fiber

A complex research was carried out to evaluate the combined effect of radiation (1keV X-ray, 50 Gy/s dose rate and total dose from 1.5 KGy to 1 MGy) and heating up to 300°C, for different types of optical fibers [48]. The results of this investigation indicated that no unitary behavior with temperature during radiation exposure can be predicted in the case of PSC, Ge-doped, P-doped, Fluorine-doped optical fibers, as in some situations (fiber compositing, temperature range, total dose) the sample heating has no effect in compensating the defects generation, while in some others RIA increases or decreases with the temperature increase. In any case, some of the study conclusions refer (i) to the possible use of such fibers in radiation dosimetry, especially at low doses, and (ii) to the limited length of fiber which can be incorporated into

A recent contribution to the use of optical fibers in radiation dosimetry refers to some studies carried out in cooperation with a team working at the European Synchrotron Radiation Facility, in Grenoble on UV multimode optical fibers subjected to synchrotron radiation [51]. In this experiment were tested five types of commercially available UV optical fibers and offline measurements concerning the degradation of the optical fibers transmission in the UVvisible spectral range were done, as color centers developed upon exposure to synchrotron radiation. The measurements were performed for different doses: 5, 10, 30, 60, 200, 400, 1000 and 2000 Gy. The radiation induced optical attenuation was monitored in relation to recovery phenomenon both at room temperature and after samples heating to 560 K. The change of optical transmission and the increase of the attenuation at specific wavelengths (λ = 215 nm; λ = 229 nm; λ = 248 nm; λ = 265 nm; λ = 330 nm) were performed using the setup presented in **Figure 4**. The measurements were done with a dedicated software control developed under LabVIEW, by using a broadband UV-visible light source, a sensitive optical fiber spectrometer,

irradiation dose graph indicates a linear dependency up to the dose of 300 kGy.

increases their radiation sensitivity [50].

44 Radiation Effects in Materials

distributed radiation sensing systems.

and an optical fiber multiplexer.

**Figure 4.** The sketch of the measuring setup: (1) light source; (2) optical fiber attenuator; (3) spectrum of the light source; (4) optical fiber multiplexer; (5) optical fiber sample absorption spectrum; (6) optical fiber mini spectrometer; (7) laptop; (8) connecting optical fibers; (9) irradiated optical fiber samples. I, multiplexer input; O, multiplexer output.

The graphical user's interface is illustrated in **Figure 5**. The multiplexer is employed to connect different tested samples to the light source and the spectrometer and help for the determination of the optical absorption from 215 nm to 600 nm. The operator can preset the number of averaging cycles, the box car value and can select the wavelengths of interest to be monitored. Of interest for these tests was to monitor specific wavelength associated to the presence of color centers in glass fibers. By observing the dependency of the optical absorption on the total irradiation dose at the specified wavelengths (**Figure 6**) can be estimated the linearity of this dependency and the spectral interval over which a saturation effect occurs. This can help to evaluate the possible use of these optical fibers in radiation dosimetry, at specified dose rates.

**Figure 5.** The LabVIEW graphical user's interface for the experimental setup (Courtesy of Laura Mihai).

46 Radiation Effects in Materials

**Figure 6.** The dynamics of the color center formation as function of the dose (i.e. 5 Gy and 2000 Gy in this case) for the five tested optical fibers, at λ = 215 nm, λ = 248 nm, λ = 265 nm, λ = 330 nm: (a) SFS400/440T (Fiberguide Industries Inc.); (b) UVS400/480 (Fiberguide Industries Inc.); (c) HPSUV400P (Oxford Electronics); (d) FVP400/UVM (Polymicro Technologies); (e) FVP400/UVMI (Polymicro Technologies).

As a premiere, the use of THz spectroscopy and imaging to assess the synchrotron radiation induced changes in the core and coating of the investigated optical fibers (**Figure 7**) was reported. This approach makes possible the "visualization" of the dielectric constants change of the irradiated materials.

**Figure 7.** The THz spectral signal of the core (a) and coating (b) of an irradiated UV optical fiber, for two synchrotron radiation doses: 5 Gy and 2000 Gy (Courtesy of Laura Mihai).

The potential to employ P-doped core multimode optical fibers as X-ray (1 keV) radiation detectors for doses up to 3 kGy, under different dose rates (1, 10, 50 Gy/s) was studied by monitoring in real time the RIA in the spectral range from 200 to 900 nm. The results indicated a sub linear dependence of the irradiation induced attenuation with the dose and dose rate. The temperature did not change RIA during the irradiation for values between 5 and 50°C. The highest radiation sensitivity was observed at 300 nm, ~0.60 dB/m−1 Gy−1 [52].

For the case RIA values during the irradiation is dependent on the radiation dose and exhibit a recovery after the exposure is interrupted, a differential scheme can be applied when the measurand is represented by the difference of RIA at two wavelengths, λ = 413 nm and λ = 470 nm, respectively [53].

Another novelty recently introduced refers to the test of gamma radiation on perfluorinated polymer optical fibers (pPOF). These results complement the investigations previously reported in literature on the spectral characteristics of gamma irradiated PMMA optical fibers. In this case, commercially available MM perfluorinated fiber GigaPOF-50SR from Chromis Fiberoptics were exposed to gamma ray at a dose rate of 5.7 kGy/h for total doses of 1, 5, 20, 50 and 100 kGy. The irradiation took place at maximum temperature of 32°C, and the samples were measured before and after the irradiation using a ν-OTDR from Luciol Instruments, operating at 1310 and 1550 nm [54]. In addition, strain tests were also performed to evaluate the mechanical degradation of the polymer fiber under gamma irradiation. For doses up to 5 kGy the attenuation vs. the dose presents a linear dependency with a radiation sensitivity of 0.096 ± 0.006 dB m-1 kGy−1 at 1310 nm, and 0.25 ± 0.05 dB m-1 kGy−1 at 1550 nm. The obtained results suggest the possible use of these optical fibers in radiation dosimetry. The dynamics of the color centers formation under gamma irradiation was investigated by on-line measure‐ ments and by monitoring RIA change at several wavelengths (λ = 420, 525, and 750 nm). The highest radiation sensitivity was noticed at λ = 420 nm (up to 0.5 kGy) dose, while the best linearity response of RIA vs. dose was obtained at λ = 750 nm for a dose reaching 2.5 kGy [55].

The last decade recorded as a breakthrough the use of sapphire optical fibers in radiation environments, as sapphire supports very high operating temperatures and presents minor optical transmission changes when exposed to ionizing radiation over a wide spectral range [56]. Recently, sapphire optical fibers were subjected to neutron flux of 1.5 × 1012 n cm−2 s−1 and a gamma dose rate of 84 kGy/hr (dose in sapphire) for a total neutron fluence of 1.1 × 1017 n cm −2 and total gamma dose of 1.8 MGy [57]. The optical attenuation in the sapphire fiber was measured on-line over the 500–2200 nm spectral range. The major RIA occurs below the 500 nm measuring limit. A change of RIA was noticed as the sample was heated to 1000°C, under gamma irradiation [58].

The use of optical fibers for distributed measurements in ionizing radiation environments became a hot topic in the last years as several tests were run and some possible applications were suggested: Raman and Brillouin strain/ temperature sensing [10, 59]; Rayleigh temper‐ ature sensing [60]. Tests were performed on standard communication, highly doped GeO2, Fdoped optical fibers [10, 59] and (PSC), Ge-doped, radiation hardened and Al-doped optical fibers [60], at dose rates of 700 Gy/h [60], 1.5 kGy/h [10], 28 kGy/h [59], and total doses of 110 kGy [60], 618 kGy [10], 10 MGy [59]. RIA proved to be the major challenge in using optical fibers distributed Brillouin temperature sensors, as the operating distance is reduced to several hundreds of meters due to irradiation [59]. Limitations in temperature monitoring are present also in the case of Rayleigh-based setup [60]. Temperature measurements using Raman scattering encounters some difficulties as the temperature evaluation uncertainty is quite high upon irradiation [10].

The complementary aspect of interest is represented by the possible use of radiation sensitive optical fibers for distributed dosimetry. Two approaches were proposed to be used: (i) the optical time domain reflectometry – OTDR [61], (ii) the optical frequency domain reflectome‐ tery – OFDR [62]. In both experiments the fiber samples were subjected to gamma irradiation: P-doped optical fibers [61] and standard communication, Al-doped, and P-doped optical fibers [62], at dose rates 590 Gy/h at 30°C and 605 Gy/h at 80°C, total dose of about 71 kGy [62], and dose rate of 23 mGy/s, for a total dose of 300 Gy [61]. The OTDR approach exhibits a limited spatial resolution for distributed dosimetry. Depending on the optical fiber type, the inter‐ rogating instrument dynamic range and the dose, the usable length of the dosimetric fiber is limited to several centimeters [62].

### **2.3. Rare earth-doped optical fibers**

**Figure 7.** The THz spectral signal of the core (a) and coating (b) of an irradiated UV optical fiber, for two synchrotron

The potential to employ P-doped core multimode optical fibers as X-ray (1 keV) radiation detectors for doses up to 3 kGy, under different dose rates (1, 10, 50 Gy/s) was studied by monitoring in real time the RIA in the spectral range from 200 to 900 nm. The results indicated a sub linear dependence of the irradiation induced attenuation with the dose and dose rate. The temperature did not change RIA during the irradiation for values between 5 and 50°C.

For the case RIA values during the irradiation is dependent on the radiation dose and exhibit a recovery after the exposure is interrupted, a differential scheme can be applied when the measurand is represented by the difference of RIA at two wavelengths, λ = 413 nm and λ = 470

Another novelty recently introduced refers to the test of gamma radiation on perfluorinated polymer optical fibers (pPOF). These results complement the investigations previously reported in literature on the spectral characteristics of gamma irradiated PMMA optical fibers. In this case, commercially available MM perfluorinated fiber GigaPOF-50SR from Chromis Fiberoptics were exposed to gamma ray at a dose rate of 5.7 kGy/h for total doses of 1, 5, 20, 50 and 100 kGy. The irradiation took place at maximum temperature of 32°C, and the samples were measured before and after the irradiation using a ν-OTDR from Luciol Instruments, operating at 1310 and 1550 nm [54]. In addition, strain tests were also performed to evaluate the mechanical degradation of the polymer fiber under gamma irradiation. For doses up to 5 kGy the attenuation vs. the dose presents a linear dependency with a radiation sensitivity of 0.096 ± 0.006 dB m-1 kGy−1 at 1310 nm, and 0.25 ± 0.05 dB m-1 kGy−1 at 1550 nm. The obtained results suggest the possible use of these optical fibers in radiation dosimetry. The dynamics of the color centers formation under gamma irradiation was investigated by on-line measure‐ ments and by monitoring RIA change at several wavelengths (λ = 420, 525, and 750 nm). The highest radiation sensitivity was noticed at λ = 420 nm (up to 0.5 kGy) dose, while the best linearity response of RIA vs. dose was obtained at λ = 750 nm for a dose reaching 2.5 kGy [55].

The last decade recorded as a breakthrough the use of sapphire optical fibers in radiation environments, as sapphire supports very high operating temperatures and presents minor

The highest radiation sensitivity was observed at 300 nm, ~0.60 dB/m−1 Gy−1 [52].

radiation doses: 5 Gy and 2000 Gy (Courtesy of Laura Mihai).

nm, respectively [53].

48 Radiation Effects in Materials

Generally, radiation hardening tests of rare earth-doped optical fibers were performed in relation to their possible use in space applications such as inter-satellite communications and fiber optic gyroscopes (FOGs) applications [63–65]. The investigations focused on the radiation induced absorption in the optical fiber and on changes of the emission efficiency. Tests were carried out under gamma ray [63, 65, 66], neutrons [65], protons [65–67], or X-ray [66] exposure. The reported studies indicate that:

**•** annealing and photobleaching can contribute to partial recovery of the irradiation induced effects [65, 67, 68].

Tests on photobleaching of two Erbium-doped fibers (EDFs) subjected to 1.3 and 2.24 kGy gamma irradiation were carried out at two laser wavelengths (532 and 976 nm). A higher efficiency was achieved with the shorter wavelength excitation. The annealing effect induced by the 976 nm laser is comparable to that present in the case of thermal annealing at 500 K [69].

In another experiment, an EDF was tested under electron irradiation (beam energy 1.2 MeV, total dose 10 kGy), and the output power, noise figure and the central wavelength were measured after the irradiation, with the pump at 980 nm and detection at 1550 nm. The central wavelength did not change after irradiation, while the output power and noise figure were deteriorated (i.e. the output power dropped from 10 to –60 dBm for the same pump level). Within 2 weeks, the two parameters partially recovered [70].

Single mode and multi-mode Yb-doped optical fibers, acting as amplifiers at 1064 nm, were subjected to gamma rays and mixed gamma-neutron irradiation, up to a total dose of 1 Gy(Si) [71]. It was noticed a linear decrease of the output power with the irradiation dose. A slight recovery was observed at room temperature, after 20 hours.

In his PhD thesis, Fox [72] concluded that EDFs are more radiation sensitive than Yb3+-doped fibers, and the most radiation hardened to gamma ray are optical fibers of Er3+/Yb3+ co-doped type. In this investigation, the radiation induced degradation increases with the increase of the dose rate.

Optical fiber preforms of Yb-free aluminosilicate core, Yb-doped Al-free silicate core, Ybdoped alumino-silicate cores and Yb-free germanosilicate core produced by MCVD and solution-doping techniques were irradiated by 45 kV X-rays, at ~2.5 Gy(SiO2)/ min, for doses up to 0.3–0.5 kGy [73]. The effects of the irradiation were studied by thermally stimulated luminescence (TSL) and optical absorption measurements.

Investigations were carried out to evaluate the influence of H2-loading of EDFs, under pumping at 980 and 1480 nm, as the samples were subjected to gamma irradiation, having doses from 0.1 to 10 kGy. One such sample was a H2-loaded EDF, while the other was H2-free carbon-coated [74]. At 980 nm pumping a photobleaching effect was observed which increases the efficiency of the process especially in the H2-loaded optical fiber. No such effect was present with the pump radiation of 1480 nm. H2-loading and the use of a hermetical coating of the optical fiber, which prevents H2 diffusion, produce a radiation resistant EDF [75].

One approach to enhance the radiation resistance of the optical amplifier consists in the use of Er-doped-nanoparticles optical fibers [76]. Another proposed method is based on the doping of the optical fiber core with Ce, reducing in this way the radiation sensitivity [77].

Tests on a thulium doped optical fiber amplifier were performed under neutron irradiation and a 17.1 dB was observed for a dose of 720 Gy, which is close to the computed values [78].

The development of Bi co-doped silica optical fibers [79] having an extensive emission operation range (from 1100 to 1800 nm) called researchers attention on their investigation under ionizing radiation. Tests run under gamma irradiation, dose rate – 5.5 kGy/h and maximum total dose – 50 kGy, on Bismuth/Erbium/Ytterbium co-Doped Fiber – BEYDF ([Bi] ~ 0.07, [Er] < 0.1, [Al] ~ 0.35, [Ge] ~ 1.18, [Yb] ~0.02 atom%, respectively, indicated the formation of bismuth related active center (BAC), as the absorption at 830nm is increased significantly, while the absorption at longer wavelength diminishes [80].

In the case of Bi/Al-co-doped silica optical fibers the fluorescence peak increases with the increase of the gamma dose (dose rate, 800 Gy/h; maximum total dose, 3 kGy), when the sample is pumped at 980 nm. The preform of the investigated materials had the following concentra‐ tions: Si—28 mol/% (core), Ge— 6 mol/% (core), O—66 mol/% (core and inner layer), Bi—0.016 mol/% (core and inner layer), and Al—0.04 mol/% (core and inner layer). It is presumed that this enhancement of the photoluminescence signal upon irradiation is due to creation of subvalence Bi ions [81].

Another investigation was focused on the effect of gamma irradiation (dose rate – 5.5 kGY/h, total doses of 1, 5, 15, 30 and 50 kGy) on samples of Bismuth/Erbium co-doped fiber (BEDF). The irradiation has significantly increased unsaturable absorption by about 8 dB. This corresponds to a very significant unsaturable attenuation coefficient change of ~32 dB/cm. The results indicate that the saturable absorption of the BEDF at 830 nm is also increased by about 4 dB. This corresponds to a significant saturable attenuation coefficient change of 16 dB/cm. The increase in saturable pump absorption implies that the irradiation has significantly increased the number of bismuth related active centers (BAC-Si). In this case the overall emission at 1430 nm (which is related to BAC-Si) is only slightly decreased while the unsa‐ turable absorption is significantly increased. A good radiation survivability of the BEDF for emission or amplification was noticed [82].


**4. Formulation of nanoemulsions**

#### **4.1. Materials used in preparation of nanoemulsions**

Nanoemulsions are prepared using oils, surfactants and co-surfactants and aqueous phase [59]. Oils used in nanoemulsions preparation include Captex 355, Captex 8000, Witepsol, Myritol 318, Isopropyl myristate, Capryol 90, Sefsol-218, triacetin, isopropyl myristate, castor oil, olive oil, etc. Solubility of the drug in the oil phase is an important criterion for the selection of oils. This is particularly important in the case of oral formulation development, as the ability of nanoemulsion to maintain the drug in solubilized form is greatly influenced by the solubility of the drug in the oil phase. While water-in-oil nanoemulsions are better choice for hydrophilic drugs lipophilic drugs are preferably solubilized in oil-in-water nanoemulsions. Drug loading in the formulation is a very critical design factor in the development of nanoemulsions for poorly soluble drugs, which is dependent on the drug solubility in various formulation components. An understanding of factors influencing drug loading capacity while maintain‐ ing the capability of the system to undergo monophasic dilution with water and minimizing the tendency for drug precipitation or crystallization in diluted systems is essential to the design of stable and appropriately low-volume nanoemulsion systems for drug delivery applications [60,61]. Edible oils are not frequently useful due to their poor ability to dissolve large amounts of lipophilic drugs. Moreover, formulation of nanoemulsion with oil of low drug solubility would require incorporation of more oil to incorporate the target drug dose, which in turn would require higher surfactant concentration to achieve oil solubilization, which might increase the toxicity of the system. Novel semi-synthetic medium chain deriva‐ tives (as amphiphilic compounds) having surfactant properties are progressively and effec‐ tively replacing the regular medium chain triglyceride oils [62,63].

Surfactants used for stabilizing nanoemulsions may be non ionic, zwitterionic, cationic and anionic. The surfactants may include Capryol 90, Gelucire 44/14, 50/13, Cremophor RH 40, Imwitor 191, 742, 780 k, 928, 988, Labrafil CS, M, 2125 CS, Lauroglycol 90, PEG MW > 4000, Plurol Oleique CC 497, Poloxamer 124 and 188, Softigen 701, 767, Labrasol, Cremophor EL, Tween 20, Tween 60, and Tween 80, etc. Components of nanoemulsion-based systems are associated with toxicity concerns. Large amounts of surfactants may cause gastrointestinal and skin irritation when administered orally and topically, respectively. Therefore, the proper selection of surfactants is essential. Rational use of the minimum concentration of the surfactant in the formulation is advocated. Nonionic surfactants are relatively less toxic than their ionic counterparts and typically have lower critical micelle concentration (CMCs). Also, o/w nanoemulsion dosage forms for oral or parenteral use based on nonionic surfactants are likely to offer *in vivo* stability [64]. Therefore, proper selection of surfactants is a crucial factor. Another important criterion is the selection of surfactant with proper hydrophile-lipophilebalance (HLB) value. Hydrophilic surfactants and co-surfactants are considered to prefer the interface and to lower the necessary energy to form the nanoemulsions, thereby improving the stability. For instance, the required HLB value to form o/w nanoemulsion is greater than 10 [65]. The right blend of low and high HLB surfactants leads to the formation of a stable nanoemulsion upon dilution with water. The type and nature of the surfactant is also an important factor for consideration; nonionic surfactants are usually selected since they are known to be less affected by pH and changes in ionic strength, are generally regarded as safe, and are biocompatible; ionic surfactants are less commonly used due to toxicological concerns. Solubilization of oil with the surfactant is also an important factor. It is not necessary that the same surfactant that has good solubilizing power for drugs would have equally good affinity for the oil phase. Surfactant–oil miscibility can thus give an initial indication on the possibility of nanoemulsion formation with this system.

Cosurfactants are added to obtain nanoemulsion systems at low surfactant concentration [66]. Short-to medium-chain-length alcohols (C3–C8) are commonly added as cosurfactants, which further reduce the interfacial tension and increase the fluidity of the interface [67,68]. They also increase the mobility of the hydrocarbon tail and allow greater penetration of the oil into this region. Alcohols may also increase the miscibility of the aqueous and oily phases due to its partitioning between these phases. Co-surfactants used in nanoemulsions include Transcutol P, glycerin, ethyleneglycol, ethanol, propanol, ethanol, isopropyl alcohol, n-butanol, PEG 400, Carbitol, and propylene glycol. Nanoemulsion area is often used as the assessment criterion for the evaluation of cosurfactants. The larger the size of the nanoemulsion field, the greater the nanoemulsification efficiency of the system.

Moreover, the most important criterion for selection of all the nanoemulsion components is that all the excipients should be pharmaceutically acceptable for oral administration or topical application, etc., depending upon the requirement and falling under GRAS category.

#### **4.2. Methods of preparation of nanoemulsions**

**•** Use of a large concentration of surfactant and cosurfactant necessary for stabilizing the nano

**•** Nanoemulsion stability is influenced by environmental parameters such as temperature and

**•** Lack of understanding of the mechanism of production of submicron droplets and the role

**•** Lack of demonstration of the benefits that can be obtained from using nanoemulsions when

**•** Lack of understanding of the interfacial chemistry that is involved in production of

Nanoemulsions are prepared using oils, surfactants and co-surfactants and aqueous phase [59]. Oils used in nanoemulsions preparation include Captex 355, Captex 8000, Witepsol, Myritol 318, Isopropyl myristate, Capryol 90, Sefsol-218, triacetin, isopropyl myristate, castor oil, olive oil, etc. Solubility of the drug in the oil phase is an important criterion for the selection of oils. This is particularly important in the case of oral formulation development, as the ability of nanoemulsion to maintain the drug in solubilized form is greatly influenced by the solubility of the drug in the oil phase. While water-in-oil nanoemulsions are better choice for hydrophilic drugs lipophilic drugs are preferably solubilized in oil-in-water nanoemulsions. Drug loading in the formulation is a very critical design factor in the development of nanoemulsions for poorly soluble drugs, which is dependent on the drug solubility in various formulation components. An understanding of factors influencing drug loading capacity while maintain‐ ing the capability of the system to undergo monophasic dilution with water and minimizing the tendency for drug precipitation or crystallization in diluted systems is essential to the design of stable and appropriately low-volume nanoemulsion systems for drug delivery applications [60,61]. Edible oils are not frequently useful due to their poor ability to dissolve large amounts of lipophilic drugs. Moreover, formulation of nanoemulsion with oil of low drug solubility would require incorporation of more oil to incorporate the target drug dose, which in turn would require higher surfactant concentration to achieve oil solubilization, which might increase the toxicity of the system. Novel semi-synthetic medium chain deriva‐ tives (as amphiphilic compounds) having surfactant properties are progressively and effec‐

Surfactants used for stabilizing nanoemulsions may be non ionic, zwitterionic, cationic and anionic. The surfactants may include Capryol 90, Gelucire 44/14, 50/13, Cremophor RH 40, Imwitor 191, 742, 780 k, 928, 988, Labrafil CS, M, 2125 CS, Lauroglycol 90, PEG MW > 4000,

**•** Limited solubility capacity for high melting substances.

compared with the classical macroemulsion systems.

**4.1. Materials used in preparation of nanoemulsions**

tively replacing the regular medium chain triglyceride oils [62,63].

of surfactants and cosurfactants.

90 Application of Nanotechnology in Drug Delivery

**4. Formulation of nanoemulsions**

droplets.

nanoemulsions.

pH.

As nanoemulsions are non-equilibrated systems [69-71], and so their preparation involves the input of a large amount of either energy or surfactants and in some cases a combination of both. As a result, high energy or low energy methods can be used in their formulation [70]. Although high energy emulsification method is traditionally used for the preparation of nanoemulsion formulation but low emulsion emulsification method now create an attraction due to their wide application and advantages as a formulation and stability aspects. Generally, energy is usually required in emulsion formulation because the process may be non-sponta‐ neous. The production of nanoemulsions costs more energy than that required to produce macroemulsions. Presence of surfactants help lower the surface tensions between oil and water. Small molecules such as non-ionic surfactants lower surface tension more than poly‐ meric surfactants such as poly (vinyl alcohol). Another important role of the surfactant is its effect on the interfacial dilatational modulus [72]. During emulsification an increase in the interfacial area takes place and this causes a reduction in surface excess. The equilibrium is restored by adsorption of surfactant from the bulk, but this takes time (shorter times occur at higher surfactant activity). Because of the lack or slowness of equilibrium with polymeric surfactants, dilatational modulus will not be the same for expansion and compression of the interface [72]. In practice, surfactant mixtures are used and these have pronounced effects on surface tension and dilatational modulus. Some specific surfactant mixtures give lower surface tension values than either of the two individual components. Polymer-surfactant mixtures may show some synergistic surface activity. An important role of the emulsifier is to prevent shearinduced coalescence during emulsification. The requirement is that the continuous phase has a significant excess of surfactant. This excess enables new surface area of the nano-scale droplets to be rapidly coated during emulsification, thereby inhibiting shear-induced coales‐ cence. This excess is generally in the form of surfactant micelles in the continuous phase. These micelles dissociate into monomers that rapidly adsorb onto the surfaces of newly created droplets [71].

*<IP_ADDRESS>. Phase Inversion Temperature (PIT) method*

This method employs temperature-dependent solubility of non-ionic surfactants, such as polyethoxylated surfactants, to modify their affinities for water and oil as a function of the temperature. It has been observed that polyethoxylated surfactants tend to become lipophilic on heating owing to dehydration of polyoxyethylene groups. This phenomenon forms a basis of nanoemulsion fabrication using the PIT method. In the PIT method, oil, water and nonionic surfactants are mixed together at room temperature. This mixture typically comprises o/w microemulsions coexisting with excess oil, and the surfactant monolayer exhibits positive curvature. When this macroemulsion is heated gradually, the polyethoxylated surfactant becomes lipophilic and at higher temperatures, the surfactant gets completely solubilized in the oily phase and the initial o/w emulsion undergoes phase inversion to w/o emulsion. The surfactant monolayer has negative curvature at this stage [75]. At an intermediate temperature (also termed HLB temperature), the non-ionic surfactant has similar affinity for aqueous and oily phase, and this ternary system has extremely low interfacial tension (in the order of 10−2– 10–5 mNm−1) and spontaneous curvature typically reaches zero [83,84]. The ternary system at this stage typically consists of a D-phase bicontinuous microemulsion or a mixture of a Dphase bicontinuous microemulsion and lamellar liquid crystalline phases. It has been observed that nanoemulsions with very small droplet size and polydispersity index can be generated by rapid cooling of the single-phase or multiphase bicontinuous microemulsions maintained at either PIT or a temperature above PIT (transitional-phase inversion) [76]. Nanoemulsions can also be generated by rapidly diluting the single bicontinuous microemulsions with the aqueous or oil phase (catastrophic phase inversion) to obtain either o/w nanoemulsion or w/o nanoemulsion. It has been observed that the characteristics of the nanoemulsion are mainly dependent on the structure of the surfactant at HLB temperature (bicontinuous or lamellar) and also on the surfactant/oil ratio. Initially, PIT method was believed to be useful for fabricating o/w nanoemulsions. However, in recent years, the application of the PIT method has been established for fabricating w/o emulsions and nanoemulsions. It is important to note that the use of lipophilic polyethoxylated surfactants and appropriate modifications in the

Nanoemulsions — Advances in Formulation, Characterization and Applications in Drug Delivery

http://dx.doi.org/10.5772/15371

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typical PIT protocol are required for obtaining w/o nanoemulsions [82].

*<IP_ADDRESS>. Phase Inversion Composition Method (Self-nanoemulsification Method)*

The solvent displacement method for spontaneous fabrication of nanoemulsion has been adopted from the nano-precipitation method used for polymeric nanoparticles. In this method, oily phase is dissolved in water-miscible organic solvents, such as acetone, ethanol and ethyl methyl ketone. The organic phase is poured into an aqueous phase containing surfactant to yield spontaneous nanoemulsion by rapid diffusion of organic solvent. The organic solvent is removed from the nanoemulsion by a suitable means, such as vacuum evaporation [78-81].

This method generates nanoemulsions at room temperature without use of any organic solvent and heat. Forgirani *et al.* observed that kinetically stable nanoemulsions with small droplet size (~50 nm) can be generated by the stepwise addition of water into solution of surfactant in

*<IP_ADDRESS>. Solvent displacement method*

#### *4.2.1. Low energy methods*

As the name suggests, low-energy emulsification methods require low energy for the fabrica‐ tion of nanoemulsions. These methods are mainly dependent on modulation of interfacial phenomenon/phase transitions and intrinsic physicochemical properties of the surfactants, coemulsifiers/co-surfactants and oil to yield nano-sized emulsion droplets. The lower energy method, also called the condensation method, is based on the phase transitions taking place during the emulsification process [73,74]. These phase transitions result from changes in the spontaneous curvature of the surfactant and can be achieved (i) at constant composition by changing the spontaneous curvature of non-ionic surfactants with temperature, the wellknown Phase Inversion Temperature, PIT, widely used in industry [75,76] or (ii) at constant temperature by varying the composition of the system by the Emulsion Inversion Point (EIP) method [77-79]. In other words, low-energy emulsification method was developed according to the phase behavior and properties of the constituents, to promote the formation of ultrasmall droplets [80,81]. These low-energy techniques include self-emulsification, phase transition and phase inversion temperature methods [82]. The low energy method is interest‐ ing because it utilizes the stored energy of the system to form small droplets. This emulsifica‐ tion can be brought about by changing the parameters which would affect the hydrophilic lipophilic balance (HLB) of the system like temperature, composition, etc. [83,84]. The limitations include complexity, precise approach required and use of synthetic surfactants. In a nutshell, the most commonly used low-energy emulsification methods include:

#### *<IP_ADDRESS>. Phase Inversion Temperature (PIT) method*

due to their wide application and advantages as a formulation and stability aspects. Generally, energy is usually required in emulsion formulation because the process may be non-sponta‐ neous. The production of nanoemulsions costs more energy than that required to produce macroemulsions. Presence of surfactants help lower the surface tensions between oil and water. Small molecules such as non-ionic surfactants lower surface tension more than poly‐ meric surfactants such as poly (vinyl alcohol). Another important role of the surfactant is its effect on the interfacial dilatational modulus [72]. During emulsification an increase in the interfacial area takes place and this causes a reduction in surface excess. The equilibrium is restored by adsorption of surfactant from the bulk, but this takes time (shorter times occur at higher surfactant activity). Because of the lack or slowness of equilibrium with polymeric surfactants, dilatational modulus will not be the same for expansion and compression of the interface [72]. In practice, surfactant mixtures are used and these have pronounced effects on surface tension and dilatational modulus. Some specific surfactant mixtures give lower surface tension values than either of the two individual components. Polymer-surfactant mixtures may show some synergistic surface activity. An important role of the emulsifier is to prevent shearinduced coalescence during emulsification. The requirement is that the continuous phase has a significant excess of surfactant. This excess enables new surface area of the nano-scale droplets to be rapidly coated during emulsification, thereby inhibiting shear-induced coales‐ cence. This excess is generally in the form of surfactant micelles in the continuous phase. These micelles dissociate into monomers that rapidly adsorb onto the surfaces of newly created

As the name suggests, low-energy emulsification methods require low energy for the fabrica‐ tion of nanoemulsions. These methods are mainly dependent on modulation of interfacial phenomenon/phase transitions and intrinsic physicochemical properties of the surfactants, coemulsifiers/co-surfactants and oil to yield nano-sized emulsion droplets. The lower energy method, also called the condensation method, is based on the phase transitions taking place during the emulsification process [73,74]. These phase transitions result from changes in the spontaneous curvature of the surfactant and can be achieved (i) at constant composition by changing the spontaneous curvature of non-ionic surfactants with temperature, the wellknown Phase Inversion Temperature, PIT, widely used in industry [75,76] or (ii) at constant temperature by varying the composition of the system by the Emulsion Inversion Point (EIP) method [77-79]. In other words, low-energy emulsification method was developed according to the phase behavior and properties of the constituents, to promote the formation of ultrasmall droplets [80,81]. These low-energy techniques include self-emulsification, phase transition and phase inversion temperature methods [82]. The low energy method is interest‐ ing because it utilizes the stored energy of the system to form small droplets. This emulsifica‐ tion can be brought about by changing the parameters which would affect the hydrophilic lipophilic balance (HLB) of the system like temperature, composition, etc. [83,84]. The limitations include complexity, precise approach required and use of synthetic surfactants. In

a nutshell, the most commonly used low-energy emulsification methods include:

droplets [71].

*4.2.1. Low energy methods*

92 Application of Nanotechnology in Drug Delivery

This method employs temperature-dependent solubility of non-ionic surfactants, such as polyethoxylated surfactants, to modify their affinities for water and oil as a function of the temperature. It has been observed that polyethoxylated surfactants tend to become lipophilic on heating owing to dehydration of polyoxyethylene groups. This phenomenon forms a basis of nanoemulsion fabrication using the PIT method. In the PIT method, oil, water and nonionic surfactants are mixed together at room temperature. This mixture typically comprises o/w microemulsions coexisting with excess oil, and the surfactant monolayer exhibits positive curvature. When this macroemulsion is heated gradually, the polyethoxylated surfactant becomes lipophilic and at higher temperatures, the surfactant gets completely solubilized in the oily phase and the initial o/w emulsion undergoes phase inversion to w/o emulsion. The surfactant monolayer has negative curvature at this stage [75]. At an intermediate temperature (also termed HLB temperature), the non-ionic surfactant has similar affinity for aqueous and oily phase, and this ternary system has extremely low interfacial tension (in the order of 10−2– 10–5 mNm−1) and spontaneous curvature typically reaches zero [83,84]. The ternary system at this stage typically consists of a D-phase bicontinuous microemulsion or a mixture of a Dphase bicontinuous microemulsion and lamellar liquid crystalline phases. It has been observed that nanoemulsions with very small droplet size and polydispersity index can be generated by rapid cooling of the single-phase or multiphase bicontinuous microemulsions maintained at either PIT or a temperature above PIT (transitional-phase inversion) [76]. Nanoemulsions can also be generated by rapidly diluting the single bicontinuous microemulsions with the aqueous or oil phase (catastrophic phase inversion) to obtain either o/w nanoemulsion or w/o nanoemulsion. It has been observed that the characteristics of the nanoemulsion are mainly dependent on the structure of the surfactant at HLB temperature (bicontinuous or lamellar) and also on the surfactant/oil ratio. Initially, PIT method was believed to be useful for fabricating o/w nanoemulsions. However, in recent years, the application of the PIT method has been established for fabricating w/o emulsions and nanoemulsions. It is important to note that the use of lipophilic polyethoxylated surfactants and appropriate modifications in the typical PIT protocol are required for obtaining w/o nanoemulsions [82].

#### *<IP_ADDRESS>. Solvent displacement method*

The solvent displacement method for spontaneous fabrication of nanoemulsion has been adopted from the nano-precipitation method used for polymeric nanoparticles. In this method, oily phase is dissolved in water-miscible organic solvents, such as acetone, ethanol and ethyl methyl ketone. The organic phase is poured into an aqueous phase containing surfactant to yield spontaneous nanoemulsion by rapid diffusion of organic solvent. The organic solvent is removed from the nanoemulsion by a suitable means, such as vacuum evaporation [78-81].

#### *<IP_ADDRESS>. Phase Inversion Composition Method (Self-nanoemulsification Method)*

This method generates nanoemulsions at room temperature without use of any organic solvent and heat. Forgirani *et al.* observed that kinetically stable nanoemulsions with small droplet size (~50 nm) can be generated by the stepwise addition of water into solution of surfactant in oil, with gentle stirring and at constant temperature [77]. Although the components used in the aforementioned investigation were not of pharmaceutical grade, the investigation opened doors to design pharmaceutically acceptable nanoemulsions using a similar approach. The spontaneous nano-emulsification has been related to the phase transitions during the emulsi‐ fication process and involves lamellar liquid crystalline phases or D-type bicontinuous microemulsion during the process [77].

**4.3. Formulation factors that affect the stability of nanoemulsions**

formulation for the delivery of pharmaceuticals.

molecules needed to stabilize the nano droplets.

**5. Characterization of nanoemulsions**

others [93]:

Although nanoemulsions enhance the physical as well as chemical stability of drugs, stability of drug product is one of the problems associated with the development of nanoemulsions [88-91]. Stability studies are performed on nanoemulsions by storing them at refrigerator and room temperatures over a number of months. The viscosity, refractive index and droplet size are determined during this period of storage. Insignificant changes in these parameters indicate formulation stability. Accelerated stability studies can also be performed on the nanoemulsions. In this instance, nanoemulsion formulation are kept at accelerated tempera‐ tures and samples withdrawn at regular intervals and analyzed for drug content by stability indicating assay methods. The amount of drug degraded and remaining in nanoemulsion formulation is determined at each time interval [92]. Stability of nanoemulsion formulation may be enhanced by controlling factors such as type and concentration of surfactant and cosurfactant, type of oil phase, methods used, process variables and addition of additives [88-93]. Overall nanoemulsion formulation may be considered as effective, safe and patient compliance

Nanoemulsions — Advances in Formulation, Characterization and Applications in Drug Delivery

http://dx.doi.org/10.5772/15371

95

Factors to be considered during preparation of nanoemulsion include the following among

**a.** The prime requirement in nanoemulsion production is that an ultra low interfacial tension should be attained at the oil water interface, so surfactants must be carefully chosen. **b.** Concentration of surfactant must be high enough to provide the number of surfactant

Characterization of nanoemulsions involves the physical and chemical tests related to oral liquid dosage forms which includes compatibility of the nanoemulsion components, isotro‐ picity of the formulation, assay, uniformity of content, appearance, pH, viscosity, density, conductivity, surface tension, size and zeta potential of the dispersed phase etc. with respect to the effect of the composition on physical parameters [94-104]. Differential scanning calo‐ rimetry (DSC) provides information on the interactions of different components and polari‐ zation microscopy using crossed polarizers is employed to confirm isotropicity of the formulation [99]. The process of self-nanoemulsification can be evaluated by visual assess‐ ment. Its efficiency would be estimated by determining the rate of emulsification and droplet size distribution. Turbidity measurements are carried out to determine the rapid equilibrium reached by the dispersion and reproducibility of this process. The droplet size of the emulsion is a crucial factor in self-nanoemulsification performance because it determines the rate and extent of drug release as well as absorption. Photon correlation spectroscopy (PCS) and light scattering techniques like static light scattering (SLS), dynamic light scattering (DLS) are a useful method for determination of nanoemulsion droplet size [100]. Viscosity, conductivity

**c.** The interface must be flexible to promote the formation of nanoemulsion.

#### *4.2.2. High energy methods*

High-energy emulsification methods make use of devices that use very high mechanical energy to create nanoemulsions with high kinetic energy. The high-energy method utilizes mechanical devices to create intensely disruptive forces which break up the oil and water phases to form nano-sized droplets. This can be achieved with ultrasonicators, microfluidiser and high pressure homogenisers [71,85,86]. Particle size here will depend on the type of instruments employed and their operating conditions like time and temperature along with sample properties and composition [87]. These methods include high-pressure homogeniza‐ tion and ultrasonic emulsification. High-pressure homogenization is the most common method used for the fabrication of nanoemulsions. During high-pressure homogenization, the coarse macroemulsion is passed through a small orifice at an operating pressure in the range of 500 to 5000 psi. During this process, several forces, such as hydraulic shear, intense turbu‐ lence and cavitation, act together to yield nanoemulsions with extremely small droplet size. The resultant product can be re-subjected to high-pressure homogenization until nanoemul‐ sion with desired droplet size and polydispersity index is obtained [71]. Micro-fluidization employs a high-pressure positive displacement pump operating at very high pressures, up to 20,000 psi. This pump forces macroemulsion droplets through the interaction chamber consisting of a series of micro-channels. The macroemulsion flowing through the microchan‐ nels collides with high velocity on to an impingement area resulting in very fine nanoemul‐ sions. The nanoemulsions with desired size range and dispersity can be obtained by varying the operating pressure and the number of passes through interaction chambers like highpressure homogenization. Ultrasonic emulsification uses a probe that emits ultrasonic waves to disintegrate the macroemulsion by means of cavitation forces. By varying the ultrasonic energy input and time, the nanoemulsions with desired properties can be obtained [85-87]. High-energy emulsification methods can be employed to fabricate both o/w and w/o nanoe‐ mulsions. High-pressure homogenization and microfluidization can be used for fabrication of nanoemulsions at laboratory and industrial scale, whereas ultrasonic emulsification is mainly used at laboratory scale. In addition, high-energy methods require sophisticated instruments and extensive energy input, which considerably increases the cost of nanoemulsions fabrica‐ tion. This is particularly significant in the pharmaceutical sciences [85-87]. High energy methods allow for a greater control of particle size and a large choice of composition, which in turn controls the stability, rheology and colour of the emulsion. Although high-energy emulsification methods yield nanoemulsions with desired properties and have industrial scalability, they may not be suitable for thermolabile drugs such as retinoids and macromo‐ lecules, including proteins, enzymes and nucleic acids. Moreover, high energy methods alone normally do not yield oil droplets (<100 nm).

#### **4.3. Formulation factors that affect the stability of nanoemulsions**

oil, with gentle stirring and at constant temperature [77]. Although the components used in the aforementioned investigation were not of pharmaceutical grade, the investigation opened doors to design pharmaceutically acceptable nanoemulsions using a similar approach. The spontaneous nano-emulsification has been related to the phase transitions during the emulsi‐ fication process and involves lamellar liquid crystalline phases or D-type bicontinuous

High-energy emulsification methods make use of devices that use very high mechanical energy to create nanoemulsions with high kinetic energy. The high-energy method utilizes mechanical devices to create intensely disruptive forces which break up the oil and water phases to form nano-sized droplets. This can be achieved with ultrasonicators, microfluidiser and high pressure homogenisers [71,85,86]. Particle size here will depend on the type of instruments employed and their operating conditions like time and temperature along with sample properties and composition [87]. These methods include high-pressure homogeniza‐ tion and ultrasonic emulsification. High-pressure homogenization is the most common method used for the fabrication of nanoemulsions. During high-pressure homogenization, the coarse macroemulsion is passed through a small orifice at an operating pressure in the range of 500 to 5000 psi. During this process, several forces, such as hydraulic shear, intense turbu‐ lence and cavitation, act together to yield nanoemulsions with extremely small droplet size. The resultant product can be re-subjected to high-pressure homogenization until nanoemul‐ sion with desired droplet size and polydispersity index is obtained [71]. Micro-fluidization employs a high-pressure positive displacement pump operating at very high pressures, up to 20,000 psi. This pump forces macroemulsion droplets through the interaction chamber consisting of a series of micro-channels. The macroemulsion flowing through the microchan‐ nels collides with high velocity on to an impingement area resulting in very fine nanoemul‐ sions. The nanoemulsions with desired size range and dispersity can be obtained by varying the operating pressure and the number of passes through interaction chambers like highpressure homogenization. Ultrasonic emulsification uses a probe that emits ultrasonic waves to disintegrate the macroemulsion by means of cavitation forces. By varying the ultrasonic energy input and time, the nanoemulsions with desired properties can be obtained [85-87]. High-energy emulsification methods can be employed to fabricate both o/w and w/o nanoe‐ mulsions. High-pressure homogenization and microfluidization can be used for fabrication of nanoemulsions at laboratory and industrial scale, whereas ultrasonic emulsification is mainly used at laboratory scale. In addition, high-energy methods require sophisticated instruments and extensive energy input, which considerably increases the cost of nanoemulsions fabrica‐ tion. This is particularly significant in the pharmaceutical sciences [85-87]. High energy methods allow for a greater control of particle size and a large choice of composition, which in turn controls the stability, rheology and colour of the emulsion. Although high-energy emulsification methods yield nanoemulsions with desired properties and have industrial scalability, they may not be suitable for thermolabile drugs such as retinoids and macromo‐ lecules, including proteins, enzymes and nucleic acids. Moreover, high energy methods alone

microemulsion during the process [77].

94 Application of Nanotechnology in Drug Delivery

normally do not yield oil droplets (<100 nm).

*4.2.2. High energy methods*

Although nanoemulsions enhance the physical as well as chemical stability of drugs, stability of drug product is one of the problems associated with the development of nanoemulsions [88-91]. Stability studies are performed on nanoemulsions by storing them at refrigerator and room temperatures over a number of months. The viscosity, refractive index and droplet size are determined during this period of storage. Insignificant changes in these parameters indicate formulation stability. Accelerated stability studies can also be performed on the nanoemulsions. In this instance, nanoemulsion formulation are kept at accelerated tempera‐ tures and samples withdrawn at regular intervals and analyzed for drug content by stability indicating assay methods. The amount of drug degraded and remaining in nanoemulsion formulation is determined at each time interval [92]. Stability of nanoemulsion formulation may be enhanced by controlling factors such as type and concentration of surfactant and cosurfactant, type of oil phase, methods used, process variables and addition of additives [88-93]. Overall nanoemulsion formulation may be considered as effective, safe and patient compliance formulation for the delivery of pharmaceuticals.

Factors to be considered during preparation of nanoemulsion include the following among others [93]: