1.

Introduction to the Pharmaceutical Industry

Pharmaceutical industry refers to the healthcare field in which discovery, production, and
distribution of vital medicinal substances are emphasized. Such products include synthetic small
molecules and biological therapies (Dailey, 2026). Being a major healthcare sector with highly
regulated operations, products within the pharmaceutical industry are known to impact the lives
of end-users. Consequently, various downstream operations such as crystallization, filtration,
and chromatography must be considered as crucial unit operations in order to isolate APIs from
crude byproducts or cell debris of reactions. The purity of API is considered to be of utmost
importance in this regard since it will determine the product's safety, as well as its economic
feasibility as an output.
In the context of these industrial processes, leaching is seen as a double-edged sword in that it
not only serves as an advantage but also poses some potential risks in quality management.
During upstream operations, leaching acts as an important solid-liquid extraction technique
whereby bioactive materials are separated from natural solid media through diffusion into liquid
solvents, all through temperature and solid particle size manipulation (Geankoplis, 2003).
On the contrary, in downstream storage and bioprocessing operations, E&L can become a
significant threat to contamination through leaching. In this case, dangerous chemicals or heavy
metal contaminants may accidentally leach from single-use bioreactor plastics, processing
membranes, or vial seals right into the sensitive drug formulation, thereby compromising the
stability and integrity of the drug substance itself (Leachables and Extractables in Bioprocessing
- Eppendorf Ireland, 2019).

2. Specific Applications of Leaching

The extraction of herbal and botanical substances acts as a fundamental industrial application
of solid-liquid leaching, a technique in mass transfer aimed at selectively extracting bioactive
secondary metabolites in the form of polyphenols, flavonoids, and alkaloids among others from
botanical tissues (Sasidharan et al., 2010). The entire mechanism operates through a series of
successive physical processes, whereby the solvent is made to diffuse through the porous
structure of the botanical material and dissolves the internal constituents present within the
cellular structures while transporting the solutes from a region of higher to lower concentrations
due to a high concentration gradient (Didem VEREP et al., 2023). Although the traditional
industrial approach relies on the use of large vessels for extended periods of maceration,
percolation, or even Soxhlet extraction processes, the current manufacturing units have adopted
the engineering approaches to intensify mass transfer (Cao et al., 2025). Such techniques
include the use of Microwave-Assisted Extraction (MAE), where the electromagnetic waves
induce rapid heating inside the plant cells leading to evaporation and rupturing of cellular
membranes, hence fast extraction (Shehnu et al., 2025).
The starting material used as feedstock to these bioleaching systems involves a variety of
vegetative plant structures, whereby volatile oils are sourced from leaves, structural alkaloids
from roots and rhizomes, and polar compounds and thermolabile antioxidants from fruits/peels
(Ghenabzia et al., 2023; Khan et al., 2024). For the improvement of mass transfer efficiency in
favor of high extraction yields, these botanicals have to be subjected to physical processing
methods (Sasidharan et al., 2010). This involves grinding of the raw materials to an even
particle size ranging between (
100μm−2mm)
for maximum surface area, short internal diffusion distances, and cell wall disruption, alongside
appropriate drying techniques to regulate moisture levels and enzymatic activities (Sasidharan
et al., 2010; Ghenabzia et al., 2023).
The choice of the extracting solvent entirely depends on the chemical polarity of the plant
extractives, based on the fundamental concept of "Like dissolve Like," (Abubakar & Haque,
2020). Water, alcohol, or aqueous alcohol mixtures serve as hydrophilic solvents to separate
highly polar molecules such as flavonoids with the preference for ethanol due to its lower boiling
point, making the extraction process more efficient and effective at removing impurities since it
does not permit bacterial presence (Sasidharan et al., 2010; Abubakar & Haque, 2020). Fatty
acids can be extracted using lipophilic extractants such as hexane. Green technology makes
use of supercritical carbon dioxide
CO
2
along with a polar organic co-solvent, for example, ethanol (Sasidharan et al., 2010; Didem
VEREP et al.,, 2023).
The operating conditions need to be strictly controlled according to the particular type of
extraction method, primarily because most of the plant-derived substances are susceptible to
heat and undergo thermolytic reactions during the process (Shen et al., 2023). In conventional
maceration, extraction takes place under ambient conditions (temperature:
20°∁−30°∁
, and pressure : atmosphere pressure) but at extended periods of two to five days (Abubakar &
Haque, 2020). On the other hand, supercritical fluid extraction (SFE) occurs at moderate
temperatures (
31℃−60℃
) but under high pressures (
80−350 bar
), whereas pressurized liquid extraction (PLE) is carried out at subcritical temperatures of up to
150℃
, and under high pressures to keep the solvent in the liquid phase. However, for substances
such as anthocyanins, the temperature needs to be carefully controlled to avoid spontaneous
chemical degradation (Didem VEREP, 2023; Shehu et al.,, 2025).
The chief product extracted during the process of leaching is referred to as miscella since it is
rich in solutes. The subsequent stages involved in the processing include vacuum evaporation,
spray drying, or freeze drying for the purpose of removal of the solvent residues (Abubakar &
Haque, 2020; Cao, 2025). The end product will be in the form of either a concentrated fluid or a
resin concentrate such as an essential oil or oleoresin. In other cases, the products may include
pure powder extracts standardized to certain chemical markers including vitexin, quercetin, or
ginsenosides (Cao et al., 2025; Shehu, n.d.). The process of extraction is central to multibillion-
dollar industry markets, which include nutraceuticals, pharmaceuticals, or cosmeceuticals (Khan
et al., 2024). Following the principles of green chemistry, the contemporary approach to the
development of leaching processes enables the production plants to achieve substantial time
savings, reduced energy consumption, and elimination of VOC emissions (Shen et al., 2023;
Khan et al., 2024).
 3. Purpose of the Leaching Process
The first and foremost function of the leaching procedure in herbal and botanical production is to
develop a highly efficient mass transfer separation process, which would ensure isolation of
important bioactive secondary metabolites from crude plant solids (Belwal et al., 2018). In
industry, plant tissues are considered to form a complicated matrix of dense and rigid cellulose-
based cell walls, which serve as natural barriers trapping various therapeutically valuable
compounds such as polyphenols, flavonoids, alkaloids, glycosides, and essential oils (Ali et al.,
2026). Leaching may be viewed as a crucial chemical engineering operation, based on
utilization of a certain type of liquids used as solvents capable of penetrating this porous
medium (Belwal et al., 2018). As a result of significant concentration gradients between different
phases, the required solutes are able to dissolve from cellular vacuoles to become available for
diffusion and subsequent separation (Belwal et al., 2018).
Aside from the aforementioned mass transfer processes, the business objective behind this
solid-liquid extraction process entails providing quality-standardized extracts that meet the
requirements of multi-billion dollar global industries ranging from nutraceuticals,
pharmaceuticals, and cosmeceuticals (Belwal et al., 2018). To maximize the aforementioned
objective, process engineers adjust key variables such as solvent polarity, contact time, and
temperature in order to attain an exact baseline purification that avoids undesirable
macromolecules, heavy waxes, and proteins (Belwal et al., 2018). Moreover, through the
application of state-of-the-art process intensification technology such as Supercritical Fluid
Extraction (SFE) and Microwave-Assisted Extraction (MAE), the objective behind the process
extends to maximize raw material efficiency and biological potency of heat-sensitive compounds
(Belwal et al., 2018; Ali et al., 2026). The latter approach is in full consonance with green
chemistry objectives since it considerably reduces processing time, reduces industrial energy
usage, and substitutes hazardous VOC solvents with environmentally-friendly ones that result in
no trace of toxic chemical residues in the final product (Ali et al., 2026).

1. Recovery of valuable compounds

Botanical leaching is based on the primary purpose of transporting and extracting the low-
concentrated bio-active substances in bulk form through the cellular matrix (Belwal et al., 2018).
Plants produce several types of compounds like polyphenols, flavonoids, alkaloids, and
polysaccharides, which are trapped in cell vacuoles (Ali et al., 2026). The process of leaching is
a crucial step where the cellular walls are either broken or permeated using an appropriate
leaching fluid (Belwal et al., 2018). By applying concentration gradient techniques, target
compounds diffuse from the cellular wall to the liquid solvent, making it possible for the
manufacturer to isolate the beneficial compound from plants (Belwal et al., 2018).
2. Purification
During leaching, separation and purification occur through the adjustment of extraction
processes in order to take advantage of the differential solubilities of the desired compounds
and cellular residue (Belwal et al., 2018). Through the careful manipulation of the solvent type,
polarity, and temperature during extraction, the process ensures that selective solubility of
certain groups of chemical compounds occurs (Belwal et al., 2018). For example, tuning the
solvent enables the extraction of the target compounds and initial purification even from raw
samples, thereby reducing the molecular composition prior to further chromatographic
separation processes (Ali et al., 2026).
3. Removal of impurities
The exclusion of unnecessary macro-compounds and structural impurities from raw botanicals
is another equally significant target that should be achieved by a successful leaching procedure
(Belwal et al., 2018). In raw plant material, there are a lot of insoluble substances, waxy
compounds, and proteins, as well as cellulose structures, which have no therapeutic
significance and may disrupt formulations (Belwal et al., 2018). Using solid-liquid separation
methods, such compounds are left on as a solid matrix while the liquid extract is collected, free
of structural impurities (Belwal et al., 2018).
4. Improvement of Product Quality
Leaching itself controls the quality of the resulting product through the maintenance of chemical
purity and biological activity of the plant materials that are volatile or fragile (Belwal et al., 2018).
Many essential components of plants are heat labile, which means they can be oxidized,
transformed, or broken down during exposure to high temperatures and harsh processing
environments (Ali et al., 2026). The application of contemporary intensification technologies in
leaching, including microwave or supercritical fluid extraction (SFE), enables reducing
temperatures during the extraction process to ensure heat stability of the components (Belwal et
al., 2018; Ali et al., 2026).
5. Waste Minimization
Contemporary leaching processes in industry tend to emphasize waste reduction via efficiency
and green chemistry practices (Ali et al., 2026). Traditional plant-based extraction processes
involve huge amounts of hazardous VOC waste production because of inefficient solvent
processes (Belwal et al., 2018). Adoption of green extractants such as biodegradable and
reusable solvent alternatives significantly reduces environmental waste chemicals, reduces the
carbon footprint of industry, and makes sure that the exhausted solid biomaterial does not have
any chemical waste residue on it (Ali et al., 2026).

The continuous counter-current multi-stage leaching procedure works based on the sequential
displacement of a previously processed solid raw material input feed in the direction of the
extractor downwards with fresh liquid solvent flowing upwards (Geankoplis, 2003; Richardson
et al., 2002). The aforementioned counter-current flow scheme guarantees a constantly high
concentration gradient, enabling a maximum amount of solute extraction to occur at a lower
solvent usage level (Mullin, 2001; Richardson et al., 2002). The solid bed moves further in the
downward direction and loses more and more of its solute content until finally being
mechanically discharged in the form of a dry solid cake via a rake-and-pump unit situated at the
bottom of the equipment (Geankoplis, 2003). At the same time, the liquid, flowing upwards,
gains additional solute content during contact with the newly arriving solid stages, until exiting
the extractor through its upper side as a clear rich miscella solution which is then sent directly
into a downstream thermal recovery unit to be treated (Myerson, 2002).

5. Advantages and Disadvantages of Leaching

Leaching, also known as conventional solvent extraction, is widely employed to extract bioactive
compounds from medicinal plant materials in pharmaceutical contexts. The primary advantages
of leaching are its simplicity, low cost, and scalability, as the process primarily involves solvent
contact, heating, and mixing. However, leaching typically requires a greater volume of solvent
and extended extraction times, which can elevate energy consumption during solvent recovery
and generate increased solvent waste if recovery is inadequate (Azmir et al., 2013; Zhang et al.,
2018).
In comparison to leaching, ultrasound-assisted extraction (UAE) demonstrates greater efficiency
due to the generation of cavitation by ultrasound waves, which disrupts plant cells and enhances
the mass transfer of bioactive compounds into the solvent. UAE reduces extraction time, solvent
consumption, and energy usage, thereby offering environmental benefits. Nevertheless, UAE
necessitates specialised equipment, precise optimisation of operational parameters, and may
produce noise during operation, which can increase both cost and safety concerns (Azmir et al.,
2013; Shen et al., 2023).
There is also another modern technique known as microwave-assisted extraction (MAE), which
is quicker compared to traditional leaching since microwaves heat up the solvent and raw
material instantly. This approach can minimize both extraction time and usage of solvents,
although this technique demands careful adjustment of several parameters such as microwave
power, temperature, duration, and choice of solvent. Furthermore, the cost of equipment used in
MAE is higher, and heat-labile components could be degraded, compromising the quality of the
products (López-Salazar et al., 2023; Flórez et al., 2014).
In general, leaching is appropriate in cases where the emphasis lies on ease of implementation,
relatively cheap technology, and a large volume of production. UAE and MAE are more
productive approaches that could be referred to as green extraction methods as these methods
decrease the use of solvents and shorten extraction time (Azmir et al., 2013). Nevertheless, they
are more costly and complicated. In any case, the most preferable method should be chosen
based on specific criteria.