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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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have utilized the potential of nanocrystals in drug formulations. Products such as
TRIGLIDE, EMEND, and MEGACE ES incorporating nanocrystals have been
developed to improve the delivery and performance of drugs with low solubility,
addressing a critical need in the industry. These commercial products underscore
the successful translation of nanocrystal research into practical solutions, mark-
ing a signicant stride forward in the eld of pharmaceutical sciences.
Keywords
Nanocrystals · Nanosuspension · Poorly soluble drugs · Drug delivery · Milling ·
Nanotechnology · Bioavailability
Abbreviations
ABZ Albendazole
AFM Atomic force microscopy
API Active pharmaceutical ingredient
ATR Microattenuated total reectance
AUC Area under curve
BCS Biopharmaceutical classication system
BET Brunauer-Emmett-Teller
BRA Brinzolamide
CT Combination technology
Cur/GMs/Coll-CNCs Porous collagen cellulose nanocarrier
DSC Differential scanning calorimetry
DTA Differential thermal analysis
DTG Derivative thermogravimetry
FF Fenobrate
FTIR Fourier-transform infrared spectroscopy
HPH High pressure homogenization
LAS Liquid antisolvent
MDIs Metred-dose inhalers
MM Media milling
NCs Nanocrystals
PCS Photon correlation spectroscopy
PDI Poly dispersity index
PG-NCs Progesterone-loaded nanocarriers
RESOLV Rapid expansion of a supercritical solution into liq-
uid solvent
RESS Rapid expansion of supercritical solution
SAS Supercritical antisolvent
SCF Super critical uid
Manshi et al.
323
SDNCS Self-dispersible nanocrystals
SDS Sodium dodecyl sulphate
SEM Scanning electron microscopy
SLS Sodium lauryl sulfate
TEM Transmission electron microscopy
TGA Thermogravimetric analysis
TPGS D-α-tocopherol polyethylene glycol 1000 succinate
XRD X-ray diffraction
13.1 Introduction
Nanocrystals are nanometre-sized crystals, which implies they are nanoparticles
having crystalline properties because of the nanosizing and employing nanocrystal-
line technology leads to an improved ratio of surface area to volume and improved
dissolution rate. This, in turn, enhances the solubility of aquaphobic pharmaceuti-
cals (Jarvis etal. 2018). The difference between them emerges from the fact that
nanocrystals are wholly formed as a therapeutic agent or payload, preventing the
need for a carrier. The dispersion of drug nanocrystals in uid substances results in
what is known as “nanosuspensions,” with surface-active agents or stabilizers fre-
quently employed to stabilize crystal dispersal in liquid substances (Oliveira etal.
2022). The dispersal media may consist of non-aqueous solutions or aqueous solu-
tions. They are widely used to deliver drugs of BCS classication system, class II
and IV drugs (low solubility drugs). Nanocrystals are widely used because of their
great loading capacity and surface area; nanocrystals have intriguing features, nota-
bly their signicant adhesiveness, which leads to a high retention period at the target
location (Viswanathan etal. 2017). Nanocrystals are commonly discovered in indi-
vidual or polycrystalline forms containing rutin (avonoids) as an active compo-
nent. Furthermore, they have the necessary characteristics to be acceptable for
cutaneous applications involving poorly soluble compounds (Ran etal. 2022).
The primary benets of nanocrystals in improving oral bioavailability encom-
pass (1) elevated saturation solubility and faster dissolution rates for drugs with low
water solubility; (2) improved adherence to biological membranes, leading to pro-
longed retention in the gastrointestinal tract; and (3) nanocrystals that can be
absorbed through intestinal epithelial cells and the lymphatic pathway while main-
taining the integrity of crystalline particles (Guo etal. 2023).
Nanocrystals, with their diminutive size in the nanometre range, represent a fas-
cinating eld in drug delivery technology. Unlike nanoparticles that may require a
carrier, nanocrystals are themselves therapeutic agents or payloads, eliminating the
need for an additional component. The integration of nanocrystals into drug deliv-
ery systems results in nanosuspensions, where stabilizers or surfactants are com-
monly employed to maintain the stability of crystalline dispersions in liquid
substances (Patra etal. 2018).
Nanocrystals typically have dimensions smaller than 1μm, often being smaller
than 500nm for practical reasons. Following nanonization, these API nanocrystals
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
324
are frequently incorporated within traditional dosage unit forms like tablets, pellets,
and capsules along with intravenous suspensions. The advantages of nanocrystals
include their exceptional reproducibility and applicability to a broad spectrum of
drugs with varying solubility proles. However, the nanocrystal approach can entail
high-energy input, leading to increased production costs. The physicochemical
attributes of nanocrystals are inuenced by the type of stabilizer employed, whether
non-ionic surfactants (such as polysorbates, poloxamers, and poloxamer) or ionic
surfactants (including bile salts and alkyl-sulfonates) (Attama etal. 2016). In com-
parison with matrix nanoparticles made of lipid or polymeric matrices, nanocrystals
exhibit a signicant drug loading, closer to 100%.Thus, the fundamental benet of
nanocrystals is the minimum quantity of formulation component (excipients) uti-
lized, which allows for achieving a substantial concentration of drug at the tar-
geted site.
Nanocrystals represent a promising avenue in drug delivery technology. Their
unique properties, including size, loading capacity, and surface area, make them
well-suited for addressing challenges associated with poorly soluble drugs. While
the energy input during production and the choice of stabilizers pose considerations,
the benets, including high drug loading and minimal excipient use, underscore the
potential of nanocrystals in advancing drug delivery across various therapeutic
domains (Naduparambath etal. 2018).
The production of nanocrystals involves the utilization of drugs with low solubil-
ity, as those with high water solubility cannot be congured into nanocrystals, espe-
cially within a water-based dispersion medium. Developing formulations for poorly
soluble APIs into nanocrystals serves to address various challenges associated with
their biopharmaceutical delivery. These challenges include issues such as inade-
quate bioavailability post oral administration, limited skin penetration resulting in
low dermal bioavailability, the requirement for excessive injection volumes in intra-
venous administration, and the occurrence of undesirable adverse effects following
IV injection when conventional formulations, like solutions with dissolved drugs,
are employed. The present innovative approach of employing nanocrystals holds
promise in overcoming these obstacles and improving the efciency of drug deliv-
ery systems (Müller etal. 2011).
13.1.1 Properties ofNanocrystals
Nanocrystals have different properties from larger crystals because of their small
size and large surface area. Some of these properties are the following:
• The utilization of nanocrystals for poorly soluble pharmaceuticals can enhance
their therapeutic efcacy by augmenting their solubility rate and absorption in
the body.
• They should have a size below 1μm.
• These are characterized by their extremely small size at the nanometre scale and
exhibit enhanced dissolution behaviour, leading to a higher saturation solubility
Manshi et al.
325
compared to larger particles. This heightened solubility is advantageous, espe-
cially for poorly soluble drugs, as it can contribute to improved bioavailability
and therapeutic efcacy.
• The nanocrystals can be present in two forms: crystalline or amorphous structure.
• They provide a safe and efcient direction through the skin.
• They have high penetration power.
• They can enhance membrane penetration, permeability, and adhesion.
• The nano-crystallization of inadequately soluble drugs enhances both their phys-
icochemical stability and bioavailability (Gu etal. 2023).
13.1.2 Advantages ofNanocrystals
Improving the dissolving rate and saturation solubility presents a valuable opportu-
nity to enhance the oral bioavailability and efcacy of medications characterized by
poor solubility. The use of nanocrystals allows for drug formulations without the
need for carriers, ensuring that 100% of the formulation consists solely of the active
drug substance. Additionally, nanocrystals contribute to improved gastrointestinal
mucosal adhesion, leading to extended residency in the gastrointestinal tract and,
consequently, enhanced absorption throughout the gastrointestinal system. Notably,
nanocrystals demonstrate limited toxicity, enhancing their safety prole across vari-
ous applications. Furthermore, their versatility is highlighted by the possibility of
administering drugs through different routes, providing exibility in drug delivery
methods (Jahangir etal. 2022; Tian etal. 2021). Figure13.1 illustrates the various
advantages of nanocrystals.
13.1.3 Disadvantages ofNanocrytals (Jahangir etal. 2022; Moroz
etal. 2018)
Nanocrystals are not without drawbacks. The following are some of the issues and
limits of nanocrystals:
• Stability issues: Because of their high surface energy and reactivity, nanocrystals
are prone to aggregation, oxidation, degradation, and phase transformation.
Stability depends on molecular structure of drug.
• Casting of high-value equipment: Need of expensive equipments.
• Release issue: The key drawback is that being crystalline in nature they are ther-
modynamically stable but do not release medication fast. Solid dispersions are
formed rather than amorphous solid dispersions, which were more thermody-
namically stable but did not release the medication as fast.
• Difculties in handling and transport: Nanocrystals require handling and trans-
port equipment to minimize exposure, contamination, and damage during pro-
cessing and storage.
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
326
• Dose accuracy issues: Because nanocrystals have an uneven distribution and
poor owability, it is difcult to quantify and administer accurate medica-
tion doses.
• Toxicity concerns: Because of their potential accumulation, penetration, and
interaction with biological systems, nanocrystals may have negative conse-
quences on the environment and human health.
• Applicability: Only certain categories of drugs are suitable.
13.2 Performance Attributes ofNanocrystals
Nanosized crystals possess unique characteristics that enable them to improve the
rate of dissolution and the bioavailability of BCS class 2 and 4 drugs. The subse-
quent sections outline and briey explore the specic characteristics of nanocrystals
that contribute to their enhanced functionality.
13.2.1 Improved Dissolution Rate by Surface Area Enlargement
The Noyes-Whitney equation describes the key features of nanocrystals and their
impact on drug dissolution.
Fig. 13.1 Schematic diagram of advantages of nanocrystals
Manshi et al.
327
dC dt DA hC C
s
//=−
()
where dC/dt is the rate of dissolution of drug particles, D is the diffusion coefcient
of drug in the GI media, A is the effective surface area of the drug particles, h is the
thickness of the diffusion layer around drug particles, C
s
is the saturation solubility
of drug in solution, and C is concentration of the drug. This equation focused on
factors such as surface area and solubility and provides insights into the speed at
which a drug dissolves. The reduction in the size of a drug results in an expanded
surface area, contributing to an augmented dissolution rate. Micronization proves to
be a viable strategy for drugs where dissolution rate is crucial, effectively enhancing
bioavailability. Progressing from micronization to nanonization further increases
particle surface, leading to a more pronounced enhancement in dissolution rate. The
heightened surface energy in nanocrystals holds potential for inuencing their solu-
bility and reactivity (Murdande etal. 2015). The Noyes-Whitney equation explains
the improved rate of dissolution of nanocrystals, where heightened saturation solu-
bility of drug (C
s
) and increased surface area (A) result in an elevated dissolution
rate for drug nanocrystals (Chogale etal. 2016).
13.2.2 Increase inSaturation Solubility
The Ostwald-Freundlich equation, as expressed in Eq. 2 explicitly denes the rela-
tionship between the saturation solubility of drug and its particulate size.
l
og
//
.
CC pV RT r
s α
()
=
22303
ρ
where C
s
represents saturation solubility of drug, C
α
denotes the solubility of the
solid with larger particles, r signies the interfacial (surface) tension of the com-
pound, V is the molar volume of the particulate substance, R stands for the ideal gas
constant, T represents the absolute temperature of substance, ρ is the density of the
solid, and r denotes the radius of the particulate size. The solubility of nanocrystals
may deviate from that of bulk materials due to size and surface properties, and the
equation aids in comprehending the impact of these factors on nanocrystal solubil-
ity. The radius of nanocrystals (r) emerges as a pivotal parameter, given the small
size of nanocrystals, inuencing their solubility and interactions with the solvent
(Shegokar and Müller 2010). Acknowledging the role of temperature in nanocrystal
solubility, the equation incorporates temperature considerations, recognizing that
alterations in temperature can impact the dissolution and stability of nanocrystals
(Junyaprasert and Morakul 2015).
13.2.3 Increase inAdhesiveness
Nanocrystals of drugs exhibit enhanced afnity to tissues, contributing to an
enhanced oral absorption of poorly soluble drugs, in addition to the improvements
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
328
in the dissolution rate and saturation solubility of the drug. On the surface of the
gastrointestinal system, there is a permeable mucus layer. The nanosized particles
allow it to quickly inltrate and attach to the pore channels of the mucus layer. So,
it prolongs the time of drug in GIT, hence enhancing bioavailability and metabolism
behaviour of drugs (Junghanns and Müller 2008).
13.2.4 Increase inPermeability
Nanocrystals (NCs) within the range of 200–300nm provide benets in terms of
increased permeability through the skin and mucosal membranes. This challenge
becomes more pronounced for drugs with poor aqueous solubility. Despite the
improved permeation properties attributed to the lipophilicity of poorly water-
soluble drugs, the rate of the drug release remains a restricting factor. The improved
penetrability of drug nanocrystals is dependent on the size of the particle; the par-
ticulates smaller than 40nm were observed to penetrate the skin via the follicular
route, whereas bigger particles faced limited penetration due to the dense system of
Langerhans cells in the epidermis. Different research suggests that particles with a
size exceeding 5μm demonstrated minimal permeation through the stratum cor-
neum. Conversely, particles within the range of 500–750nm showed enhanced per-
meation into the hair follicles of human skin (Patel etal. 2018).
13.3 Preparation Techniques ofNanocrystals
There are several approaches available for producing nanocrystals with specic
shapes and sizes. Essentially, three fundamental principles can be employed: mill-
ing, precipitation methods, homogenization methods, or a combination of these
techniques. The primary methods utilized in the industry involve top-down tech-
nologies, which entail the reduction of the size of a large drug powder. In contrast,
bottom-up technologies, starting from a dissolved molecule and involving precipita-
tion, are not currently utilized in the production of commercial products, to the best
of our knowledge. This can be ascribed to difculties such as the requirement for
removing solvents, challenges in controlling the process, and the observation that
numerous poorly soluble drugs display low solubility not only in water but also in
organic substances. Figure13.2 illustrates nanocrystal preparation techniques and
schematically shows top-down and bottom-up approaches.
Various methods for producing nanocrystals are available, depending on the
nature and size of the substance. Nanocrystals can be produced using top-down
methods, bottom-up techniques, or a combination of both approaches.
• Top-down methods: This involves employing mechanical forces to reduce
larger crystals into smaller ones, using methods like milling, sonication, or high-
pressure homogenization. The top-down approach is suitable for drugs that are
Manshi et al.
329
poorly soluble in both water and organic solvents. It operates quickly and is com-
monly utilized in the production of commercially available drugs nanocrystals.
• Bottom-up methods: These include the formation of nanocrystals from smaller
molecules or atoms by chemical processes such as precipitation, sol-gel, hydro-
thermal, or solvothermal synthesis.
• Combinative techniques: These methods combine top-down and bottom-up
approaches to obtain ideal nanocrystal size, shape, and stability (Mengge etal.
2022; Kulkarni and Myerson 2017).
13.3.1 Top-Down Approaches
By exerting mechanical pressure (top-down method), bigger crystals are divided
into smaller ones in the top-down process of creating nanocrystals. This strategy
employs several techniques, including the following:
13.3.1.1 Wet Bead Milling
This process involves grinding a solid substance in a rotating container with balls or
beads to create minuscule particles. The nanocrystal particle size is mainly inu-
enced by factors such as the milling bead size (typically 0.1–20nm), the drug’s
properties, and the setup parameters. Wet bead milling is particularly effective for
producing nanocrystals of thermally unstable drugs because the absolute tempera-
ture can be regulated during the manufacturing process. It is user-friendly and yields
a consistent result. Nevertheless, the addition of wetting agents and stabilizers is
required, and multiple rotations are essential to reach the intended particle size
(Malamatari etal. 2018). The media mill (MM) comprises essential components
such as a milling chamber, milling media, recirculating chamber, motor, and cool-
ant. The processing chamber is loaded with a crude mixture of drugs, water, and
Fig. 13.2 Schematic diagram of preparation techniques of nanocrystals
13 Advances andDevelopments inFormulation ofDrug Nanocrystals
330
stabilizers. During the milling process, the motor stirs an unrened mixture of
drugs, stabilizers, and water in the milling chamber. In the end, the slurry makes up
2–30% (w/v) of the milling chamber capacity, and the milling media comprises
10–50% (w/v) of the slurry. Reduction in size is achieved through mechanical shear
and attrition, arising from collisions between a drug molecule and the milling cham-
ber components or processing media, as well as between two drug particles (Salazar
etal. 2013).
13.3.1.2 Evaporation/Condensation
This involves heating a metal to evaporate it and then condensing the vapour to
obtain nano powders. During the evaporation phase, a solution or melt containing
the material of interest is carefully subjected to controlled evaporation. This can be
achieved through various methods such as solvent evaporation or cooling. As the
solvent evaporates, the concentration of the solute increases, leading to supersatura-
tion. At a critical point, nucleation occurs, initiating the formation of nanosized
particles.
The subsequent condensation step is crucial in shaping the nanocrystals. The
vapour generated during evaporation undergoes controlled cooling or condensation,
promoting the assembly of nanoparticles. The condensation conditions, including
temperature and pressure, play an essential role in examining the nal characteris-
tics of nanocrystals (Harish etal. 2022).
13.3.1.3 High-Pressure Homogenization
High-pressure homogenization (HPH) is an additional top-down process wherein
drug molecule size reduction is achieved through shearing forces, cavitational
forces, and drug molecule colloidal system, all supported by pressurized airow
conditions. There are commonly two types of HPH procedures: microuidization
and piston gap homogenization.
In HPH process, drug suspension undergoes high-pressure homogenization by
passing through a constrained pathway in a sudden burst under elevated pressure.
The two types of HPH procedures are described as follows:
1. Microuidization, alternatively called air-jet milling or jet stream homogeniza-
tion, encompasses the breaking down of particles within a pressurized airow
formed by the merging of two uid streams at a pressure of 1700bar.
2. The process of piston-gap homogenization employs elevated pressure to propel
a uid suspension through a restricted channel or a narrow gap in a pipeline. This
process typically consists of three stages:
(a) Distribution of powdered medication in either a pure solution or a solution
that includes a stabilizing agent.
(b) Minimizing the size of molecules by either rapidly shearing them or using
low-pressure homogenization.
(c) Application of pressurized homogenization to attain the desired particle size
and size distribution.
Manshi et al.
331
In summary, HPH is a top-down technique employing high-pressure conditions,
and its variations, microuidization and piston-gap homogenization, involve spe-
cic processes to reduce drug particle size effectively.
High-pressure homogenization in water, referred to as Dissocubes
®
, is a method
that yields nanosuspensions with exceptional dissolution and disintegration proper-
ties. The particles take on a cuboid shape, and the trade name for these prepared
nanosuspensions is Dissocubes
®
. This innovative process avoids material erosion
and contamination from production/processing equipment, maintaining levels typi-
cally below 1ppm, falling within an acceptable range. The technique allows for the
preparation of highly concentrated or diluted nanosuspensions, handling drug
amounts ranging from 1 to 400mg/mL.This is particularly relevant for drugs with
low water solubility in both aqueous and non-aqueous medium, enabling aseptic
manufacturing of nanosuspensions for subcutaneous (parenteral) administration
(Sun and Yeo 2012).
In contrast, homogenization in water-free media and mixtures of water, known as
Nanopure, prove to be more appropriate for specic administration routes. In the
development of the second generation of drug nanocrystals (Nanopure), drug sus-
pensions in organic medium, like propylene glycol, undergo homogenization
(Müller etal. 2001). Figure13.3 illustrates the preparation method of Disso cubes.
13.3.1.4 Laser Ablation
Laser ablation involves using a laser to heat a gas mixture containing a metal pre-
cursor and then cooling it to form nanoparticles. There are three categories of laser
processing durations: picosecond, nanosecond, and femtosecond. Included these,
nanoscale particles can be produced more abundantly. Particle size is inuenced by
factors such as laser intensity, scanner velocity, suspension characteristics, and
other related factors. Although there are no organic solvents used in this procedure,
a tiny amount of the medicine might experience oxidative degradation and crystal
state alterations because of using too much power (Sylvestre etal. 2011).
13.3.1.5 Ultrasound
Ultrasound proves to be an effective method for breaking down medication parti-
cles into tiny ones through the vibrations of auditory waves. By inducing acoustic
cavitational forces into a solution and quickly dispersing the drug solution, ultra-
sound has been demonstrated to enhance formation of nuclei. Its ease of use in the
laboratory and reliable reproducibility often lead to its integration with other
Fig. 13.3 Schematic representation of preparation technique of Dissocube
13 Advances andDevelopments inFormulation ofDrug Nanocrystals