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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5441_Библиотеки_им_академика_М_И_Перельмана.pdf
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processes. Ultrasound-assisted precipitation of nanoparticles inuences key pro-
cesses like mixing, nucleation, growth, and agglomeration. Factors such as the
length of the horn, immersion depth of the horn, cavitation depth, and the intensity
of ultrasonic treatment all play an essential role in examining the size of the nano-
crystals (Waard etal. 2011; Baig etal. 2021).
13.3.2 Bottom-Up Approaches
The bottom-up technique for making nanocrystals includes creating larger mole-
cules or atoms from smaller ones through chemical processes. These are a few of
the procedures this technique employs:
13.3.2.1 Precipitation
In the bottom-up technique of nanocrystal synthesis, precipitation serves a critical
function in the formation of nanocrystals. This technique involves the controlled
and gradual reduction of solutes from a solution, leading to the spontaneous nucle-
ation and growth of nanoscale particles. Typically, a supersaturated solution of the
desired material is prepared, and then, through the introduction of a precipitating
agent or by altering the environmental conditions, the solutes reach a point of satu-
ration, triggering their aggregation into nanocrystals. The selection of appropriate
precipitation conditions, such as temperature, solvent, and concentration, is vital in
determining the size, shape, and uniformity of the resulting nanocrystals (Sinha
etal. 2013). This method allows for a high degree of control over the particle size
distribution and is commonly used in the manufacturing of nanocrystals and various
applications, including drug delivery, catalysis, and advanced materials. Precipitation
in the bottom-up approach offers advantages in terms of scalability, reproducibility,
and the ability to tailor nanocrystal properties, making it a versatile and widely uti-
lized method in the eld of nanotechnology (Tran etal. 2016). The preparation
method of precipitation is shown in Fig.13.4.
13.3.2.2 Sol-Gel
In the bottom-up technique of nanocrystal synthesis, the sol-gel method serves as a
versatile and effective approach. The sol-gel process involves the transformation of
a precursor sol into a gel-like network and subsequent solid material. In the context
of nanocrystal formation, this technique starts with a solution containing precursor
molecules, often metal alkoxides or other chemical precursors. Through controlled
hydrolysis and condensation reactions, the sol evolves into a three-dimensional gel
structure with nanoscale dimensions. The gel is then subjected to further
Fig. 13.4 Schematic illustration of the precipitation technique of bottom-up approaches
Manshi et al.
333
processing, such as drying and calcination, resulting in the formation of nanocrys-
tals (Yarbrough etal. 2020). The sol-gel method provides precise control over par-
ticle size, composition, and morphology by manipulating precursor chemistry and
reaction conditions. This approach is particularly advantageous for producing nano-
crystals of various materials, including metal oxides, semiconductors, and hybrid
organic-inorganic compounds. The versatility and tunability of the sol-gel process
make it a widely employed technique in the bottom-up synthesis of nanocrystals for
applications spanning from catalysis and sensing to optoelectronics and advanced
materials (Kumar etal. 2017).
13.3.2.3 Nanoprecipitation inMicrofluidic Reactors
Nanoprecipitation in microuidic reactors represents an innovative approach within
the bottom-up technique for preparing nanocrystals. This method harnesses the
advantages of microuidic technology to precisely control the nanoprecipitation
process. In this technique, a continuous ow of a solvent containing a dissolved
precursor or drug is introduced into a microuidic channel. Simultaneously, another
continuous ow of a non-solvent, which is capable of being mixed with the solvent
but incompatible with the precursor, is introduced. The controlled mixing of these
two streams induces rapid supersaturation and leads to the spontaneous nucleation
and formation of nanocrystals. The conned and precisely regulated environment of
the microuidic reactor allows for superior control over reaction parameters, includ-
ing mixing ratios, ow rates, and residence times (Ali etal. 2009). This results in
nanocrystals with well-dened sizes, shapes, and narrow size distributions. The
nanoprecipitation in microuidic reactors method is particularly advantageous for
producing nanocrystals of materials with varying solubilities. This bottom-up tech-
nique offers scalability, reproducibility, and the ability to tailor nanocrystal proper-
ties, making it a promising method for applications such as drug delivery, imaging,
and advanced materials (Niculescu etal. 2021).
13.3.2.4 Liquid Antisolvent Precipitation
An insoluble drug-containing solution stream (organic phase) is combined with an
aqueous antisolvent to create liquid antisolvent (LAS) precipitation, which pro-
duces nanocrystals. The most often described technique of nanoprecipitation is
solution-antisolvent. This procedure is straightforward and economical because it
simply calls for the nucleation and growth processes. Two steps can be used to pre-
pare the optimized nanocrystals. Nanocrystals are precipitated and aggregated
because of this process, which also recrystallizes unstable crystal particles.
Medications that do not dissolve in water or are not insoluble in non-aqueous sol-
vents should not be formulated with organic solvents due to the issue of solvent resi-
dues (Bajaj etal. 2012).
13.3.2.5 Precipitation Assisted by Acid-Base Method
In the CO2-assisted precipitation technique, acid-base reactions are commonly uti-
lized. This includes dispersing the medication in a mildly acidic solution for the
acid phase and in a weakly basic solution containing a stabilizer for the base phase.
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
334
Nanocrystals of the drug are formed through vapour effervescence by gradually
introducing the acid phase into the base phase, generating carbon dioxide. This
method is environmentally friendlier as it does not require the use of carbon-based
solvents, although it is applicable only to poorly soluble medications whose solubil-
ity depends on pH and remains stable during acid-base interactions (Pınar et al.
2023). This includes dissolving the drug in a mild acid solution for the acid phase
and a weak base solution containing a stabilizer for the base phase. This method is
environmentally friendly as it eliminates the need for organic solvents. However, it
is only suitable for medications that are insoluble and exhibit solubility dependence
on pH, while also remaining stable during acid-base interactions.
13.3.2.6 High Gravity-Controlled Precipitation
This method enhances the uniformity and density of drug nanocrystals through
advancements in the gravity-controlled precipitation process. The primary factors
inuencing particle size include the concentration of reactants, rotation speed, and
volumetric ow rate. Continuous mixing and reaction of the drug solution within
the apparatus are facilitated by this technique. Nevertheless, the practical imple-
mentation of this approach is limited due to persistent nucleation caused by local-
ized oversaturation near the turbulent edge during mixing (Pardhi etal. 2018).
13.3.2.7 Supercritical Fluid (SCF) Method
This method entails the dissolution of pharmaceuticals in a supercritical uid, such
as CO
2
, and the formation of nanocrystals through the quick evaporation of the
supercritical uid. This evaporation occurs as the uid is sprayed through a nozzle
with a narrow aperture under lowered pressure. Two techniques, rapid expansion of
supercritical solution (RESS) and supercritical antisolvent (SAS), utilize supercriti-
cal uids in line with their role in the crystallization process. An enhancement of the
rapid expansion of supercritical uid method has been developed, resulting in the
rapid expansion of a supercritical solution into a liquid solvent (RESOLV) approach.
In RESOLV, the propeller is positioned in the air for the former and in an aqueous
solution for the latter, depending on distinct nozzle placements (Ahmadi et al.
2019). The preparation method of supercritical uid method is shown in Fig.13.5.
13.3.2.8 Emulsion Polymerization Method
An oil-in-water (O/W) emulsion is generated by dissolving the active pharmaceuti-
cal ingredient (API) in organic solvents with high volatility or solvents that are
partially blended with water as the dispersion phase. Subsequently, the carbon-
based (organic) solvent is homogenized drop by drop into liquid state, typically
incorporating emulsiers to facilitate easy control of the emulsion droplet size. The
process of obtaining drug nanocrystals involves evaporating, mixing, and extracting
the emulsions. The nal product’s quality is signicantly affected by factors such as
the emulsier, shearing rate, vaporization rate, temperature gradient, and pH scale.
While this emulsion polymerization process is well-suited for laboratory opera-
tions, it may not be practical for large-scale pilot production without the need of
ultrasound or homogenization due to its requirements (Boles etal. 2016).
Manshi et al.
335
The key benet of top-down approaches as compared to bottom-up techniques is
the ability to create nanosuspensions with higher loading of drug. Furthermore,
these methods avoid the use of severe organic solvents, because the solvent in which
the medication is distributed but not dissolvable in water for most weakly aqueous-
soluble medicines, forming top-down approaches environmentally acceptable. This
enables the production of a wide spectrum of weakly soluble APIs, referred to as
“brick dust.”
13.3.3 Combinative Technology
13.3.3.1 Nano Edge Technology
The initial combined technique developed for reducing particle size in the manufac-
ture of nanodrugs is known as nano edge technology. This method utilizes the high-
pressure homogenization (HPH) approach, complemented by the precipitation
method. In this process, precipitation is employed to form initial crystal particles,
and reducing slit obstruction in the high-pressurized airows is employed to improve
the effectiveness of reducing the particle size during the approach of homogeniza-
tion. Following this, the HPH procedure is utilized to further compress the drug
molecules, prohibiting secondary growth and addressing issues like Oswald ripen-
ing and uneven molecule size distribution and associated with the precipitation
method. This, in turn, enhances the structural stability of the nanocrystal fragments.
Additionally, for the high-energy procedure, alternative methods such as ultrasound
Fig. 13.5 Schematic representation of the supercritical uid technology
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
336
or micro uidization can be applied (Zhou etal. 2019). The preparation method of
nanoedge is shown in Fig.13.6.
13.3.3.2 Smart Crystal Technology
Smart Crystal technology comprises a primary stage of pre-treatment, succeeded by
a micronization (HPH) process. Preliminary treatment procedures, such as bead
milling, spray drying, atomization drying, or sedimentation, may precede
HPH.Acknowledged as a second-generation technique for generating nanocrystals,
Smart Crystal technology embraces a comprehensive strategy termed “collection.”
This collection functions as a set of tools to enhance technology in the creation of
drug nanocrystals and encompasses diverse methodologies, including H69, H42,
H96, and combination technology (CT) (Sun etal. 2018).
13.4 Characterization ofNanocrystals
Characterizing nanocrystals is essential to understand their properties and potential
applications. Characterization methods help researchers assess the size, shape, com-
position, crystallinity, and surface characteristics of nanocrystals. The following are
typical methods employed for the characterization of nanocrystals:
13.4.1 Particle Size andSize Distribution
The mean particle sizes and polydispersity indexes (PIs) of the nanocrystals are
determined using photon correlation spectroscopy (PCS) with the Malvern Zetasizer
3000HS (Malvern Instrument, Malvern, UK). The PI reects the variability in the
Fig. 13.6 Method of preparation of nanoedge
Manshi et al.
337
particle size distribution, with lower PI values indicating greater uniformity among
particles. A PI exceeding 0.7 signals polydispersity in the suspended particles. To
achieve an appropriate concentration for PCS measurements, a portion of the fresh
nanosuspensions is diluted with a saturated solution containing approximately
0.1wt% of stabilizer. Before size measurements, the nanosuspensions undergo son-
ication for 4min. The analyses utilize a dispersant refractive index of 1.33, and each
sample undergoes three measurements for accuracy (Yue etal. 2022).
13.4.2 SEM
SEM is an alternative microscopy approach that provides surface imaging of nano-
crystals. While it offers lower resolution than TEM, it is useful for studying the
overall morphology and size distribution of nanocrystals (Kachhadiya etal. 2022).
When transforming formulated nanosuspensions into a dried powder, either through
processes like lyophilization or spray drying, it is essential to conduct SEM analy-
sis. This analysis helps monitor changes in particle size and shape both before and
after the removal of water. Typically, clustering may occur post water removal, lead-
ing to maximization in particle size. SEM enables the observation of such altera-
tions. To mitigate the extent of particle size increases, certain inactive ingredients
are added as “protectants.” Mannitol is frequently employed as a cryoprotectant in
the lyophilization process. It undergoes recrystallization around the nanocrystals as
water is removed, preventing particle interaction and agglomeration (Hecq
etal. 2005).
While a certain level of agglomeration is acceptable if the nal particle size
remains within an acceptable range, it is crucial that the dried powder can be easily
redispersed into stable nanosuspensions. Additionally, the shape of the drug crystals
is inuenced by their crystalline structure (Thakur etal. 2020).
13.4.3 TEM
TEM is a powerful method for visualizing the size, shape, and morphology of nano-
crystals at the nanoscale. It provides high-resolution images that reveal details about
individual nanoparticles and their distribution (Rana etal. 2021). TEM (transmis-
sion electron microscopy) captures images by directing a beam of electrons through
a thin specimen, providing a detailed view of the interior of the sample. Widely
utilized in nanomedical research, this microscopy technique offers high resolution,
enabling the detailed examination of interactions between nanoparticles and cell/
tissue components. The electron beams’ remarkably short wavelength, approxi-
mately 100,000 times shorter than photons in the visible spectrum, allows for sub-
nanometre resolution, reaching about 0.2nm in conventional TEM (Malatesta 2021).
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
338
13.4.4 AFM
The morphology and topography of the CNCs are examined through AFM (atomic
force microscopy). An aqueous CNC suspension is initially dried on a glass slide for
imaging. Subsequently, scans are performed in semi-contact mode in the air using a
Nanotec Electronica scanning probe instrument based in Madrid, Spain. The AFM
imaging system allows environmental control within the chamber, allowing adjust-
ments to either ambient conditions with approximately 30% relative humidity (RH)
or to around 0.1% RH by introducing N
2
gas from liquid nitrogen boil-off into the
chamber. The AFM images are then processed using WSxM software (version 12.0)
(Bushell etal. 2021; Chen etal. 2021).
13.4.5 Surface Area andPore Size Analysis
Techniques like BET (Brunauer-Emmett-Teller) evaluation can be used to deter-
mine the dened pore size distribution and surface area of nanocrystals, which is
important for understanding their surface properties and reactivity (Uke etal. 2020).
13.4.6 Zeta Potential
The physical stability of nanocrystals is inuenced by the surface charge they carry.
Greater physical stability is observed when particles have elevated equal charges,
leading to heightened electrostatic repulsion. The measurement of particle surface
charge is best represented by “zeta potential,” which is determined by analysing the
electrophoretic mobility of particles in an electric eld. The particle charge can be
quantied in surface charge per unit through colloid titration (Dhibar etal. 2023).
Particle aggregation is less probable when particles possess a suitable zeta potential,
guaranteeing efcient electric repulsion, or when there is an ample steric barrier,
ensuring appropriate steric repulsion between them. According to the literature, a
zeta potential of at least −30mV is advised for electrostatically stabilized systems
and−20mV for sterically stabilized systems, to attain physical stability in nano-
crystal suspensions (Prasanna and Mitra 2020). The upper limit of the zeta potential
is set at +30mV.
13.4.7 DSC
Differential scanning calorimetry (DSC) is a commonly used technique to investi-
gate the thermal properties of drugs and drug nanocrystals. DSC studies are carried
out to evaluate the crystalline nature of the drug and the interactions between excipi-
ents and the drug after the production of nanocrystals. This is especially important
for drugs that exist in various polymorphic forms. Additionally, certain top-down
techniques, such as high-pressure homogenization, can lead to particles containing
Manshi et al.
339
an amorphous fraction, thereby improving saturation solubility. DSC analysis
involves examining pure drug, a physical mixture of the drug and excipients (stabi-
lizer), and the nal formulation, which may be in dried form. DSC can be classied
based on the operating mechanism into two categories: heat ux DSC and power-
compensated DSC.In heat ux DSC, two pans are placed on a thermoelectric disk
within a furnace containing the sample and an empty reference pan. The furnace is
heated at a linear rate, and heat is transferred to the sample and reference pan
through the thermoelectric disk (Kang and Kim 2023; Wadhawan etal. 2021).
13.4.8 XRD
The evaluation of nanocrystals’ morphological and polymorphic changes involves
an examination of their morphology and crystalline state (Nath et al. 2020).
Typically, the X-ray diffraction (XRD) method is employed to assess the crystallin-
ity form of the drug. Conrming the formulation of the nanocrystal is achieved by
observing changes in the polymorphic state. In this process, the X-ray diffraction
pattern of the crystalline substances is compared with that of the pure sample. Each
crystalline substance produces a unique pattern, and the amalgamation of various
substances presents its distinct pattern. The X-ray diffraction pattern of a particle
serves as a unique ngerprint for identifying the substance. The specimen is posi-
tioned on a level aluminium sample holder. Information is gathered by scanning
from 5° to 40° with 0.02° increments, and each step takes 0.5s for measurement
(Koneti etal. 2014).
13.4.9 FTIR
The FTIR technique is employed to assess the chemical characteristics of a drug and
its interactions with various excipients used in the formulation (Aguayo etal. 2018).
The samples’ spectra are captured within the range of 4000–400 cm
−1
using an
FTIR spectrophotometer (Vertex 70, Bruker Optik, Ettlingen, Germany) equipped
with a micro attenuated total reectance (ATR) accessory. The ATR unit incorpo-
rates a disc of diamond as the internal reection element, and the sample penetra-
tion depth ranges from 0.1 to 2μm. To acquire FTIR spectra at room temperature,
2μL of the samples are applied twice and dried using a triple dental syringe. The air
spectrum is utilized as a background in the FTIR analysis. The analysis of sample
spectra is performed with a resolution of 2cm
−1
and 34 scans (Valle etal. 2021).
13.4.10 Raman Spectroscopy
The Raman spectroscopy technique functions based on the principle of inelastic
scattering of monochromatic light emitted by a laser source. In this process, the
frequency of photons in the monochromatic light undergoes changes due to
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
340
interaction with the sample, a phenomenon known as inelastic scattering. The sam-
ple absorbs and then re-emits the laser photon light, resulting in a shift in the remis-
sion frequency either upwards or downwards compared to the original monochromatic
light frequency. This occurrence is referred to as the Raman effect, offering insights
into rotational, vibrational, and other low-frequency transitions within molecules
(Testa-Anta etal. 2019). During sample preparation, a minimal quantity of water is
used to mitigate water interference with Raman spectra. This spectroscopy serves as
a valuable tool for characterizing phase transitions and identifying the crystalline or
amorphous nature of various nanostructured materials, including nanoparticles and
nanocrystals. Additionally, it is employed to assess defects in nanomaterials, deter-
mine the size and shape of nanomaterials, and analyse the distribution of nanostruc-
tured materials as either homogenous or heterogeneous (Bala etal. 2020).
13.4.11 TGA
Different thermal analyses, such as thermogravimetry (TG), derivative thermogra-
vimetry (DTG), and differential thermal analysis (DTA), are utilized to evaluate the
thermal stability, crystalline properties, and pyrolysis behaviour of polymers con-
taining nanocrystals (Rana et al. 2023). Thermogravimetric analysis combines
microscopy and thermal analysis to examine and characterize materials concerning
temperature and time. Hot stage microscopy is useful for both screening and char-
acterizing polymorphs, as well as discerning the crystalline and amorphous regions
of nanocrystals (Pandi etal. 2021).
13.4.12 Permeation Study
Permeation studies are commonly carried out utilizing the Franz diffusion cell
apparatus, utilizing skin samples such as human cadaver skin, pig ear skin, rat skin,
or pig skin. The enhanced saturation solubility and dissolution of nanocrystals also
indicate heightened adherence to the skin, thus aiding in the transportation of the
drug through the skin membrane (Imono etal. 2020; Patzelt etal. 2011).
Characterizing nanocrystals often requires an integration of these methods to
attain a thorough recognition of their physical, chemical, and structural properties.
The preference of characterization methods relies on the properties and applications
of the nanocrystals under investigation.
13.5 Applications ofNanocrystals
13.5.1 Oral Delivery
The advantages of orally administering drugs are signicantly enhanced using drug
nanocrystals (NCs), especially in improving the bioavailability of poorly soluble
medications. When there is a need for a quick onset of action for such drugs,
employing drug NCs proves benecial, as observed in the case of analgesics. For
Manshi et al.
341
example, formulating the analgesic Naproxen as a nanosuspension resulted in a
reduced time to reach maximum concentration (t
max
) and an approximately threefold
increase in the area under the curve (AUC) compared to a regular suspension
(Naprosyn
®
) (Jacobs etal. 2000). This formulation not only minimizes gastric irri-
tability but also takes advantage of the adhesive properties and prolonged residence
time inherent in drug NCs. The mucoadhesiveness of these formulations can be
further enhanced by incorporating mucoadhesive polymers into the distribution
medium, providing an additional benet in manipulating bioavailability (Müller and
Jacobs 2002).
13.5.2 Parenteral Administration
Administering poorly soluble drugs parenterally, especially through intravenous
(IV) injection for practically water insoluble substances using cyclodextrins, lipo-
somes, surfactants, or cosolvents, often results in either toxic side effects or large
injection volumes. On the other side, nanosuspensions without carriers have the
potential to provide greater loading capacity than alternative parenteral application
system. When a drug is delivered as a nanosuspension, the rapid dissolution of the
nanocrystals (NCs) mimics the plasma concentration prole of a solution. The
nanosuspension showed signicantly increased tolerance, resulting in an around
twofold increase in the LD50 value (Sarnes etal. 2013; Testa-Anta etal. 2019).
13.5.3 Pulmonary Drug Delivery
Numerous essential APIs designed for pulmonary delivery face challenges due to
poor solubility in both non-aqueous media and water. This is evident in widely used
corticosteroids like beclomethasone dipropionate and budesonide. Nano-
suspensions provide an effective solution to overcome these difculties. Nebulizing
nanosuspensions generates aerosol droplets of the desired size, carrying a substan-
tial quantity of drug nanocrystals. The use of these nebulized nano-suspensions sig-
nicantly enhances the respirable fraction compared to conventional metred-dose
inhalers (MDIs). Furthermore, drug nanocrystals exhibit improved mucoadhesive-
ness, extending their time of residence on the mucosal surface of the lungs (Pardhi
and Jain 2021; Yue etal. 2022; Tuomela etal. 2016).
13.5.4 Ocular Drug Delivery
Delivering medication to the eyes poses challenges and holds promise as an exciting
area of research. Consequently, several topical formulations are under development
to address ocular disorders. However, achieving effective ocular drug delivery has
been a persistent challenge, marked by signicantly low bioavailability. Only about
5% of locally administered drugs reached to ocular tissues due to factors such as
rapid corneal drug elimination, the presence of the ocular surface epithelial barrier,
and conned absorption from the ocular fornix. Tuomela et al. developed
13 Advances andDevelopments inFormulation ofDrug Nanocrystals