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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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controlled-release matrices. Examples of such lipids comprise caprylocaproyl poly-
oxyl-8 glycerides, linoleyl polyoxyl-6 glycerides, lauroyl polyoxyl-32 glycerides,
and stearoyl polyoxyl-32 glycerides. Certain commercially accessible medications
formulated with these polymers and lipids consist of felodipine, gliclazide, ritona-
vir, verapamil, fenobrate, and enzalutamide (Siepmann etal. 2019). Inorganic sub-
stances having adsorbent qualities, such as montmorillonite and mesoporous silica,
are the carriers that recently have been recognized for their role in controlled drug
release (Sohail Arshad etal. 2021).
6.2.6 Co-processed Excipients
Co-processed excipients are utilized to enhance drug loading capacity, tensile
strength, and operational efciency, along with improving ow properties, moisture
resistance, sensitivity to lubricants, disintegration performance, and responsiveness
to strain rates. A co-processed product often consists of a mix of brittle and plastic
components that interact at the subparticle level. Melt extrusion, granulation, sphe-
ronization, co-crystallization, co-drying, co-milling, spray drying, and coprecipita-
tion are just a few examples of co-processing techniques that may be used (Saha and
Shahiwala 2009). Innovative combined excipients comprise calcium carbonate-
MCC, cellulose-lactose (Cellactose), silicied MCC, magnesium silicate-maize
starch, MCC-dicalcium phosphate dihydrate, and alpha-lactose monohydrate cross-
linked with PVP-HPMC E3 (Saha and Shahiwala 2009; Viscasillas Clerch etal.
2013; Wang etal. 2015; Rashid etal. 2011).
These multipurpose co-processed excipients might perhaps be used in continu-
ous manufacturing. During continuous manufacture, excipients are fed at the right
pace and in the right proportion; it might be expensive to dedicate a separate feeder
to each component.
Therefore, using multifunction composite excipients can signicantly contribute
to lowering both the quantity and variability of input materials in a continuous pro-
cess (Challener 2020).
6.3 Advances inTablet Manufacturing Processes
Over a period of time, routines for tablet manufacturing have been developed that
incorporate advanced granulation techniques, hot-melt extrusion, extrusion/sphe-
ronization, injection molding, spray drying, spray congealing, coprecipitation, and
nanotechnology-based methods.
6.3.1 Advanced Granulation Approaches
Granulation is a multistep process used to produce tablets. Recent advancements in
wet and dry granulation methods have successfully reduced process variability and
enhanced productivity.
N. N. Jitendra et al.
149
1. Dry Granulation
A signicant progression in dry granulation technology involves the utiliza-
tion of pneumatic dry granulation (PDG). This approach merges the conven-
tional roller compaction method with a specialized pneumatic system to create
granules that exhibit enhanced ow characteristics and compressibility. In the
context of powder dispersion granulation (PDG), a mild compressive pressure is
exerted using a roller compactor on the powder particles, leading to the forma-
tion of a consolidated mixture comprising both ne particles and granules.
Through the utilization of a pneumatic system, the granules of the intended size
range are sorted within a fractioning chamber. PDG permits the incorporation of
substantial drug quantities (ranging from 70 to 100%). Various additional bene-
ts encompass rapid processing pace; minimal to no material loss; compatibility
with drugs sensitive to moisture, solvents, or heat; enhanced ow; and compress-
ibility. However, notable limitations of this production method involve the
impact of recycling on the quality of granules and concerns related to the fragil-
ity of granules (Shanmugam 2015; Sandler and Lammens 2011).
(a) Hot-Melt Extrusion
Hot-melt extrusion (HME) engages in the mixing of formulation con-
stituents within a barrel using rotating screws at elevated temperatures. The
melted mixture is then forced through an extruder, and the resulting extru-
sions can be formed into pellets or compressed to create tablets (Bruce
etal. 2005). The quality of the prepared formulation is affected by various
factors like the rate of feeding, temperature at different points, duration of
residence, the design or velocity of the extruder screw, and the rate of cool-
ing. The pharmaceutical sector extensively investigates the application of
the HME method for crafting solid dispersions. The outcome of the hot-
melt extrusion process is an amorphous solid solution characterized by
elevated innate energy that is naturally present, resulting in enhanced drug
solubility and bioavailability. Nonetheless, this procedure requires substan-
tial energy and is unsuitable for drugs sensitive to high temperatures (Bruce
etal. 2005; Simões etal. 2019). The hot-melt extrusion (HME) approach
was employed to produce orally disintegrating tablets containing sildenal
citrate, with a focus on taste-masking. Ethyl cellulose was chosen as the
matrix material. It was noted that the taste-masking effectiveness of the
formulation is inuenced by the screw conguration, which modies the
physical condition of the active substance (Morott etal. 2015). Tablet for-
mulations employing hot-melt extrusion (HME) were developed to create
sustained-release tablets of acetohydroxamic acid and chlorpheniramine
maleate. These tablets are designed to oat in the stomach for over 24h.
Eudragit RS PO, Eudragit E PO, and sodium bicarbonate were used in the
formulation process (Fukuda etal. 2006). Tablets containing itraconazole
and nimodipine, formulated through the solid dispersion method using
HPMC acetate succinate, HPMC, and PVP, were prepared via the HME
technique. The FDA (Food and Drug Administration) granted approval to
two tablet dosage forms relying on solid dispersion technology: Viekirax/
Technivie (containing ombitasvir, paritaprevir, and ritonavir) in 2015 and
6 Advances inTablet Production andTablet Coating
150
Maviret/Mavyret (comprising glecaprevir and pibrentasvir) in 2017
(Simões etal. 2019).
(b) Pneumatic Dry Granulation (PDG)
Pneumatic dry granulation (PDG) is an innovative dry granulation tech-
nique that integrates roller compaction with a unique air sorting method to
produce granules. These granules possess an exceptional balance of ow
properties and the ability to be compressed (Shanmugam 2015). This
approach generates granules from powdered particles by rst applying a
gentle compression force using a roller compactor. As a consequence, there
is a consolidated mixture comprising a combination of ne particles and
granules. The pneumatic system in a fractioning chamber segregates the
smaller granules and ne particles by carrying them away within a stream of
gas. At the same time, the granules of the desired size advance into the frac-
tionation chamber, where they undergo compression to form tablets. The
ne particles and smaller granules carried in the gas stream are subsequently
moved to a tool like a cyclone. The granules can either be promptly recycled
or reused in the roller compactor or stored in a container for later processing,
to achieve the desired granule size (Heilakka etal. 2010). The PDG method
has shown its effectiveness in creating granules that exhibit consistent ow
characteristics across all formulations, resulting in compacts with an esti-
mated tensile strength of 0.5MPa. Furthermore, this technique allows for
the incorporation of elevated drug quantities ranging from 70 to 100%. This
is possible as satisfactory owability can be attained even with reduced roll
compaction forces (lower solid fractions) in contrast to standard roller com-
paction methods (Sandler and Lammens 2011). Apart from these advan-
tages, this technology also offers several other benets like quicker
processing, cost-effectiveness, and minimal to zero material wastage, and
the enclosed system design leads to decreased exposure to dust. However,
the potential effects of recycling on granule quality, its compatibility with
low-dose formulations, and its impact on friability and related aspects con-
tinue to be notable concerns associated with the pneumatic dry granulation
(PDG) technology. Figure 6.1 illustrated the pneumatic dry granulation
mechanism.
2. Recent Advancements in Wet Granulation
The extensively employed method is wet granulation, where granules are cre-
ated by moistening the excipients and API using a granulating liquid, optionally
with or without using a binder. Wet granulation has experienced a range of tech-
nical and technological advancements, including methods like steam granula-
tion, moisture-activated dry granulation (or moist granulation), thermal adhesion
granulation, melt granulation, freeze granulation, foamed binder (or foam granu-
lation), and reverse wet granulation.
(a) Reverse Wet Granulation
Reverse wet granulation, alternatively referred to as reverse-phase wet
granulation, is an emerging innovation within the wet granulation process. It
involves immersing the dry powder formulation in the binder liquid and then
N. N. Jitendra et al.
151
gently breaking it to form granules (Li and Reynolds 2010). As outlined by
this innovation, initially, the binder solution was prepared, followed by the
introduction of the dry powder excipients into the binder solution while
being blended within a granulator. As a different approach, the drug was
combined with a hydrophilic polymer and/or a solution of binder, creating a
slurry of drug-polymer/binder utilized as the granulating uid. This slurry
was then used to create granules by submerging a blend of additional dry
excipients into it. After drying, the wet granules that were obtained under-
went a milling process. The granules yielded by this procedure demonstrated
favorable ow and handling attributes similar to those achieved through the
wet granulation process. Moreover, tablets originating from these granules
exhibited a more consistent erosion pattern during dissolution testing in
comparison to the usual wet granulation method. The main process of gran-
ule formation in the reverse wet granulation method is believed to involve
controlled fracture (Wade et al. 2014, 2015). This method is claimed to
enhance the dissolution properties of drugs with low water solubility. It
achieves this by ensuring even dispersion of the binder, which serves as a
wetting agent. This, in turn, facilitates the effective moistening of the drug
substance throughout the granulation procedure. Figure 6.2 shows sche-
matic presentation of reverse wet granulation process. Furthermore, it raises
the probability of sufcient and consistent interaction between the pharma-
ceutical compound and the hydrophilic polymer, leading to enhanced dis-
solution. These enhanced granule attributes lead to uniform tablet
Fig. 6.1 Schematic diagram of pneumatic dry granulation
6 Advances inTablet Production andTablet Coating
152
disintegration during the dissolution process. The benets of this approach
compared to traditional wet granulation encompass the generation of com-
pact, round granules that exhibit enhanced ow characteristics. Additionally,
there is uniform saturation and disintegration of these granules. This method
might be appropriate for drugs with limited water solubility due to the close
connection between the drug and the polymer. The practicality of existing
equipment, like the high-speed mixer, is an added advantage of this method.
Nevertheless, at lower binder concentrations, this approach yields granules
with larger average mass diameter and reduced internal porosity compared
to conventional wet granulation (Shanmugam 2015).
(b) Steam Granulation
Steam granulation is an innovative method of wet granulation; steam is
used as a binding agent instead of the typical granulation liquid, which is
typically water. Pure steam is a clear gaseous substance that offers enhanced
permeability into the powder and a more advantageous heat equilibrium
throughout the drying phase. Following the steam condensation, water gen-
erates a heated, delicate layer on the powder particles. This layer necessi-
tates only a minor additional energy input for removal and undergoes
evaporation more smoothly (Rodriguez etal. 2002). This method provides
various advantages, including the effective distribution and penetration of
powder particles by steam, the creation of round granules with enhanced
surface area, and a faster, eco-friendly process without the use of organic
solvents. A high-shear mixer connected to a steam generator would be ade-
quate for executing this method. Nonetheless, signicant energy inputs are
essential for generating steam using this method. Furthermore, this proce-
dure is not appropriate for all binding agents and is responsive to heat-
sensitive drugs. The granules yielded by this technique exhibit an enhanced
dissolution rate due to their larger granule surface area in contrast to the
traditional wet granulation process (Rodriguez etal. 2002; Cavallari etal.
2002; Albertini etal. 2003; Vialpando etal. 2013a, b).
Fig. 6.2 Schematic diagram of reverse wet granulation
N. N. Jitendra et al.
153
(c) Moisture-Activated Dry Granulation (MADG)
This method is a modication of the traditional wet granulation tech-
nique. It utilizes a small amount of water to trigger binding agents and initi-
ate the agglomeration process (Ullah etal. 1987). This method consists of a
dual step: (1) moist agglomeration of the powder particles and (2) moisture
absorption or distribution. The combination of the medication, the binder,
and extra additives is made by blending with a small quantity of water, fre-
quently below 5% (with a preference for 1–4%). Agglomeration occurs
when the binder is activated by the granulating uid (water). Following the
agglomeration, moisture-absorbing materials like silicon dioxide, micro-
crystalline cellulose, etc. are added to make it easier for more moisture to
absorb. The moisture-absorbent materials remove the moisture from agglom-
erates, causing the powder mixture’s moisture content to be redistributed,
resulting in a comparatively dry granules mixture. While some of the bigger
agglomerates may break down resulting in a more evenly distributed particle
size, some smaller agglomerates may remain unchanged in size during this
moisture redistribution process (Railkar and Schwartz 2000, 2001a, b).
Using MADG for manufacturing controlled-release and immediate-release
dosage forms demonstrated the benets of wet granulation, such as enhanced
ow properties, greater compressibility, and larger particle sizes. Moreover,
this technique provides broad versatility, time and energy savings, and fewer
process variables while ensuring consistent process effectiveness (Railkar
and Schwartz 2001a, b).
(d) Melt Granulation
Melt granulation, also known as thermoplastic granulation, is a technique
that enables the compaction of powder particles utilizing binders with the
ability to melt or become soft at relatively low temperatures, typically rang-
ing from 50 to 90°C (Haramiishi etal. 1991). The last phase of the granula-
tion process involves cooling the gathered powder and subsequently
solidifying the melted or softened binding agent (Maejima etal. 1998a, b).
The inclusion of binders with lower melting points into the granulation pro-
cedure can occur in two ways: as solid particles that undergo melting as part
of the process (referred to as the melt-in technique or in situ melt granula-
tion) and as liquid molten binders, potentially with the drug dispersed within
them (known as the spray-on or pump-on technique). These approaches
offer a range of possibilities for tailoring the characteristics of the eventual
granules. To be more precise, the melt-in method within the melt granulation
process entails heating a mixture of drugs, binding agents, and extra addi-
tives to a temperature that matches or exceeds the melting point of the
binder. In contrast, the spray-on method involves the application of a melted
binding agent, potentially carrying the drug, onto the powder that is being
heated (Abberger 2001; Passerini etal. 2010; Aleksić et al. 2014). Melt
granulation serves as a suitable substitute for various wet granulation meth-
ods utilized with materials sensitive to moisture (Watanabe et al. 2016).
6 Advances inTablet Production andTablet Coating
154
Furthermore, when contrasted with the standard wet granulation procedure,
it presents numerous benets (Shanmugam 2015).
Typically, the melt granulation process doesn’t necessitate the use of
organic or aqueous solvents. This eliminates the need for managing and
recycling organic solvents, meeting environmental criteria. Additionally, the
absence of water removes the wetting and drying stages, resulting in a pro-
cess that consumes less time and energy. The melt granulation process can
effectively enhance the inadequate physical characteristics of the drug sub-
stance and improve the stability of drugs sensitive to moisture (Kowalski
etal. 2009; Shah etal. 2013). The main drawback of this method is the need
for elevated temperatures throughout the procedure that may result in oxida-
tive instability and/or deterioration of the ingredients, particularly of the
drugs that are thermolabile. In this technique, either hydrophilic or hydro-
phobic binders can be utilized. Choosing a meltable binder, regardless of
whether it has hydrophilic or hydrophobic properties, signicantly impacts
the dissolution behavior of drugs. Appropriate equipment for melt granula-
tion comprises a high-shear mixer and a uidized bed granulator (Abberger
and Henck 2000; Aoki etal. 2015; Van Melkebeke etal. 2006). Figure6.3
shows graphical presentation of melt granulation process.
(e) Foam Granulation
Comparable to spray agglomeration, the foam granulation or foamed
binder granulation process includes introducing a liquid or aqueous binder
in a foamy state, as opposed to spraying or pouring it onto the powder par-
ticles. The Dow Chemical Company (Midland, MI) initially launched this
foam binder technology in 2003 for the delivery of aqueous binder systems
in high-shear and uid bed wet granulation processes (Keary and Sheskey
2004). The binder can be introduced as foam rather than being sprayed or
poured over the moving powder particles by installing a foam generator
inside the tank containing the binder solution, where there is either a high-
shear granulator or a uid bed granulator. Utilizing the binder solution in the
form of foam rather than a spray prevents irregular and unforeseen distribu-
Fig. 6.3 Schematic diagram of melt granulation
N. N. Jitendra et al.
155
tion of the binder, which could impact tablet rmness and drug release char-
acteristics. Compared to sprayed water, the foamed binder/water has
signicantly greater surface area and overall volume. This method utilizes
the properties of the foamed binder to promote uniform allocation of the
binder across the powder particles. This is achieved even when using less
binder compared to what’s typically needed in the traditional spray granula-
tion technique. Additionally, the liquid droplets that are sprayed have a poor
spread-to-soak ratio, which means that instead of spreading on the surface of
the particles, they prefer to soak into powders and produce over-wetting,
which requires a lot of water and binder followed by drying to remove extra
water. Instead, because of the high spread-to-soak ratio of foamed binders,
which are deposited over the particles instead of being soaked, less binder is
used, and the dispersion of the binder is more evenly distributed. These ele-
ments decrease processing time while enhancing repeatability. The most
signicant benet of this technique is the removal of spray nozzles, along
with the processing variations and clogging issues they cause (Tan et al.
2013). Incorporating this technology, apart from the advantages mentioned
earlier, would prove benecial for drug formulations with high potency and
low dosage requirements because it ensures uniform drug distribution. In
addition to formulations for instant release and controlled release, water-
sensitive formulations may also be made using this technique because of the
minimal water need and quick processing time. For this technique, a foam
generator might be combined with common tools like a uid bed granulator,
high/low shear mixers, etc. Although this technique has several benets,
more research has to be done on foam quality, process variables, equipment,
ow patterns, mixing behavior, etc. Additionally, getting regulatory permis-
sion would be a major challenge (Keary and Sheskey 2004; Tan etal. 2013;
Koo etal. 2012; Rocca etal. 2015; Thompson etal. 2012).
6.4 Process Automation
Automation involves the utilization of machinery and tools to execute both physical
and cognitive tasks within a production process, substituting the need for human
involvement (Gandu etal. 2023). The growing focus on automated technology in
the pharmaceutical industry is driven by the promising trend of fully automating
tablet production. This trend is fueled by the desire for enhanced tablet quality,
streamlined manufacturing processes, and effective validation of the entire produc-
tion process. The paramount characteristic of an automated compression system lies
in its capacity for exible design, primarily concerning both the tablet press and,
more crucially, the control system. No automated compression system is suitable
for all production scenarios. In each production area, there is an existing system
already in operation, and it is the responsibility of the vendor to offer an automated
design that replicates this system through automation (Bardin etal. 2004).
6 Advances inTablet Production andTablet Coating
156
The direct compaction continuous tablet manufacturing process encompasses
unit operations such as feeder, comill, blender, and tablet press. These operations
are managed on-site through their respective user interfaces, indicating that pharma-
ceutical manufacturing plants still rely on manual or semiautomatic operation. The
existing operating system doesn’t facilitate easy data extraction, presenting a sig-
nicant obstacle to implementing a control system in pharmaceutical manufactur-
ing plants due to the lack of automation. Integrating control hardware, software, and
sensors with process equipment is a difcult endeavor because of the absence of
standardized controls in pharmaceutical equipment. Hence, there is a strong need
for a structured framework that can effectively automate a pharmaceutical plant
(Singh 2018).
6.4.1 Automation inTablet Manufacturing
The advantages of incorporating automation in tablet manufacturing are dis-
cussed below.
1. Improved material handling
Examples of material handling improvement:
The computerized systems oversee the granulation and tableting stages in the
tablet manufacturing process at Merck Sharp & Dohme (MSD) and Eli Lilly and
Company.
Advantages:
• Materials are handled without human intervention.
• The structure, situated within a three-story building, is designed to maximize
the use of gravity through vertical drops and employs pumps, vacuum sys-
tems, and bucket conveyors to facilitate the upward movement of materials
as needed.
2. Improvement in a specic step of tablet manufacturing known as “unit opera-
tions” like sieving, particle size reduction, mixing, drying, compression, coating,
and packaging
Examples include automatic weigher and recording system for weighing and
measuring, high-speed rotary press for compression, and H I-COATER for aque-
ous coating.
3. Coating process improvement
The application of a coating on tablets and pills using a coating pan relies
heavily on the operator’s skills and control.
The standard Accela Cota is designed for coating tablets or pills with aque-
ous or solvent-based lms. It features a coating pan with side vents or
perforations.
Advantages:
• Air ows in a singular direction through the tablet bed, exiting through the
perforations in the pans. This signicantly minimizes or eradicates the
rebound of atomized spray and the drying of spray droplets, a common issue
with solvent-based coating in traditional pans.
N. N. Jitendra et al.
157
• This aids in the coating process by promoting efcient drying due to the
increased airow through the bed.
• Utilized for the uninterrupted coating of lm and sugar systems.
4. Tableting Improvement
The Thomas Tablet Sentinel (TTS) is an automated tablet production unit that
incorporates real-time control and monitoring of tablet weight. This unit makes
use of readily accessible strain gauge technology, with strain gauges positioned
on the tablet machine to observe the strain generated during the compression
process. The pressure or compression force at each station is determined by the
quantity of powder in the respective die, establishing a link between compres-
sion force and tablet weight. Consequently, measuring this compression force
provides an indirect means of monitoring the weight of the tablets.
6.4.2 Fundamental Process Control Instruments
• Sensors: These are instruments designed to gauge the process variables essential
for making control determinations.
• Input-output (I-O) devices: These convert sensor signals into formats that can be
effectively processed by the computer. This category includes computer devices
such as programmable controllers, microcomputers, and minicomputers.
• Activators: They receive directives from the computer through the I-O devices
and translate them into actions executed within the process.
6.4.2.1 Automation in Direct Compaction Continuous
Pharmaceutical Manufacturing Process
If adequately automated, a centralized control platform can operate the continuous
pharmaceutical manufacturing pilot plant. Automation additionally enables the col-
lection of process data measured by sensors integrated into each unit operation. In
order to achieve full automation, it is essential to integrate the operating platform
with each unit operation of the pilot plant. Pharmaceutical unit operations can be
categorized into three groups depending on their required automation approach: (1)
eldbus connectivity; (2) serial port connectivity; and (3) OLE process control
(OPC) connectivity. Three types of communication protocols were employed to link
the unit operations with the operating platform. The integration of the feeder was
accomplished using Probus communication, while the blender and comill were
integrated using serial ports communication. OPC communication was used to inte-
grate the tablet press. Both platforms are linked to the plant through a switch, allow-
ing easy selection of either platform to operate the plant. It’s important to emphasize
that at any given time, the plant only necessitates a single control platform.
6.4.2.2 Rotary Tablet Press
Utilizing computer technology, the pharmaceutical control units, equipped with a
microprocessor, automatically rectify weight variations, monitor tablet values, and
manage the rejection of faulty tablets. Additionally, they can trigger quick-stop con-
trols if specic tolerances are exceeded.
6 Advances inTablet Production andTablet Coating