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1.2.3 Polymorphism andCrystallinity
Drugs and excipients are found in various crystalline or amorphous states based on
their chemistry and isolation methods. Molecules can arrange themselves in differ-
ent geometric congurations during crystallisation, resulting in a structure with dis-
tinct packing arrangements or orientations for the created crystals. These multiple
states are generally knownas polymorphsand this phenomenon is known as poly-
morphism. The physicochemical properties of each polymorphic form, such as
solubility and melting point, can signicantly impact stability and bioavailability.
Furthermore, polymorphism might impact the compression properties of pharma-
ceutical products, i.e. the orthorhombic form of paracetamol shows better com-
pressibility than its monolithic form due to the presence of sliding planes in the
orthorhombic form (Bastin etal. 2000).
The crystal structures of amorphous solids are typically disorganised; hence, the
shift in the physical structure of solids as the temperature rises is not that sharp and
provides a broad melting peak in differential scanning calorimetric analysis. The
temperature at which solid particles start melting is called glass transition tempera-
ture. This is another valuable preformulation feature that needs to be considered
while optimising manufacturing procedures (such as temperature selection in heat
sterilisation for injectables, wet granulation for tableting, freeze-drying of inject-
ables, etc.) since they may alter the polymorphic structure and therefore the physi-
cochemical and biological properties of the nal product (Bandopadhyay etal. 2018).
In order to guide the establishment of a manufacturing process that guarantees
the creation and maintenance of the preferred polymorph, it is crucial to determine
whether a candidate for development has the propensity to exist in different poly-
morphic states, the properties of each polymorph (melting point, density, hardness,
optical properties, hygroscopicity, solubility, stability, etc.) and the conditions under
which each may be formed. Selecting a sufciently stable polymorph at room tem-
perature is very desirable, as is dening the temperature settings (during manufac-
ture and storage) under which polymorphic change or instability could negatively
impact the efcacy, safety and stability of drug molecule (Bandopadhyay et al.
2018; Barbosa etal. 2019; Bastin etal. 2000).
1.2.4 Bulk Properties
Particle size and shape determine the dissolution rate and impact the primary and
bulk powder characteristics. Particle size and distribution, ow characteristics and
dissolution are important properties that should be researched in dissolution science
and when developing new formulations. The physicochemical features of medicinal
salts are frequently inextricably linked to their melting point. During formulation
development, low melting point APIs often show signs of plastic deformation, lead-
ing to aggregation and caking and affecting the ow and compressibility perfor-
mance. These, in turn, impact several crucial quality characteristics of the drug
K. Jain etal.
7
product (at low doses), including homogeneity of content, friability, rates of disin-
tegration and invitro dissolution (Bharate and Vishwakarma 2013).
Bastin etal. examined the physicochemical characteristics of many salts of the
antiarthritic medication RPR 200765 to highlight the signicance of ow proper-
ties. Among the four types of salt that they studied—mesylate, hydrochloride,
hydrobromide and camphor sulfonate—mesylate salt showed good handling quali-
ties, including good ow, which is necessary for the formulation stage, and nonhy-
groscopic nature, which made the production of capsules and tablets easier. The
ow properties of mesylate saltwere superior compared to the other salts investi-
gated (hydrochloride, hydrobromide and camphor sulfonate) (Bastin etal. 2000).
Most of the drugs available in the market are in a salt form, either weak bases or
acids. Consequently, it is critical to comprehend the behaviour of molecules during
ionisation at particular pH values. Therefore, to comprehend dosage form stability,
solubility, bioavailability and efcacy of drug molecules, the effects of drug ionisa-
tion, ionic strength, pH and temperature are simultaneously evaluated at the prefor-
mulation stage (Bharate and Vishwakarma 2013).
Apart from this, the stability study of active pharmaceutical ingredients, compat-
ibility studies with other excipients, hygroscopicity and degradation prole must
also be studied as part of the preformulation study to get regulatory approval for
pharmaceutical products. In summary, preformulation is a proactive stage that plays
a pivotal role in converting a novel chemical entity into a pharmaceutical product
that is stable, safe and effective for human use.
1.3 Prototype Development
Generally, ideas for the development of new products are the descriptive statements
that can be written or verbalised, and further these ideas are rened into product
concepts that involve benets of consumers based on the product characteristics.
The concepts are then developed into the prototype, which is the working model of
the nal product. Therefore, it is a crucial stage of the development of new pharma-
ceutical product, and it involves the development of the working model based on the
characteristics of the product obtained during wet lab work for its commercialisa-
tion. The ideas in the pharmaceutical industries are protected by very strong intel-
lectual property system such as patents. Intellectual property rights (IPR) are the
legal rights granted to the inventors to protect their invention for specic period, and
the patentee gets market exclusivity. IPR promotes the economic growth and healthy
competition among the scientists from the pharmaceutical research and develop-
ment eld.
There are four phases of prototype development, where phase 1 is the identica-
tion of the basic requirements for the product development, phase 2 is the prepara-
tion and implementation of the design to meet those requirements, phase 3 involves
the experiments with the prototype and phase 4 includes the revision of the proto-
type and accomplishing those requirements (Singh etal. 2017). To conceptualise a
pharmaceutical product from an idea, various parameters should be studied during
1 Advances inDevelopment ofPharmaceutical Products
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preformulation studies, including chemical nature and stability of the active phar-
maceutical ingredients. Further, the safety and efcacy during preclinical or clinical
stages are considered. During preclinical phase of drug development, biopharma-
ceutical and physiochemical characteristics of drugs are analysed to assess its
potential and to reduce the failure rate during the clinical trialas shown in Fig.1.1.
1.3.1 Experimental Design andOptimisation ofProduct
While developing pharmaceutical product, it is always desirable to establish opti-
mal and efcient process performance including improved product qualities,
enhanced process exibility and reduced environmental impact. Therefore, nding
optimal composition and establishment of processing conditions are the main objec-
tives while developing novel pharmaceutical product of desirable performance.
Experimental designs involve the strategic planning to establish optimisation proce-
dures to develop pharmaceutical formulation with desired attributes. While estab-
lishing an experimental design, the optimal conditions are established for several
factors such as temperature, concentration of excipients, pH, etc., that affect the
results or responses of a procedure (Dejaegher and Heyden 2011). During optimisa-
tion, one or more factors or independent variables are varied, and response or
dependent variables are observed. Finally, experimental domain is obtained from
Phases of
Prototype
Development
Phase 1:
Identification of basic
requirement of
pharmaceutical
products.
Phase 2:
Development of a design
to meet these
requirements.
Phase 3:
Experiment with the
prototype.
Phase 4:
Revision of prototype to
achieve requirements
identified in phase 1.
Fig. 1.1 Phases of prototype development
K. Jain etal.
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the responses of dependent variables, which showstheoptimum values of depen-
dent variabled to get the best possible product with an efcient procedure.
Experimental design involves various steps, where the rst step is identifying the
rationale of the experimentation and the kind of data desired from the experiment.
The second and third steps are the selection of the factors and responses, respec-
tively, while the fourth step is the designing of the experiments. The experiments are
replicated multiple times to obtain statistically signicant results. In nal steps,
experiments are conducted, results are analysed and conclusion is drawn. Based on
the experimental design, the process is optimised to obtain the pharmaceutical prod-
uct with the specic attributes, which further complies with the guidelines of the
regulatory bodies and meets the quality standards (Armstrong 2006; Gibson 2005).
1.3.2 Parenteral Dosage Forms
Parenteral dosage forms are administered to obtain immediate therapeutic effect,
and it includes the administration routes like subcutaneous, intravenous and intra-
muscular. However, parenteral administrations have several disadvantages such as
infection risk at the administration site, and in the case of dosing error, its effect
cannot be reversed. However, sometimes it is the preferred route of administration
due to higher bioavailability, therapeutic agent acts in seconds due to the direct
delivery to the systemic circulation and it can be administered to the unconscious
person. There are various cases where parenteral route is the only option such as
administration of insulin or paclitaxel or aminoglycoside antibiotics such as genta-
micin (Camacho Vieira etal. 2024).
Parenteral dosage forms should be free of foreign particles because they are
meant to be injected straight into the systemic circulation. In addition, there are
several additional quality-related criteria that should be considered while develop-
ing parenteral formulations. The product’s sterility is one of the most important
quality factors as the parenteral-administered formulation subjected to the systemic
circulation directly. The autoclave is commonly used technique to achieve sterility
in formulations by heating them under pressure. However, certain drugs, including
peptide and protein therapeutics, are heat-sensitive and can be deteriorated by
excessive heat or pressure; in this case, sterilisation by ltration can be used to
achieve sterility. Another factor that is considered while developing parenteral for-
mulation is the pH, which should be as close as possible to the physiological
pH.However, pH can also inuence the stability and solubility of the drug in the
solution, and in many cases the optimum pH for stability and the solubility does not
coincide with the physiological pH.In the case of difference between the physio-
logic pH and the pH of the formulation, the formulation should be adjusted to a pH
value that maintains the stability and adequate solubility of the drug while at the
same time not differing considerably from the physiologic pH.For instance, solu-
tions with pH values higher than 9 can cause tissue necrosis.
The solubility of drug moleculein the formulation is another crucial consider-
ation in the optimisation of parenteral dosage forms. Therapeutic agents can be
made more soluble by employing various techniques such as adjusting the pH of the
1 Advances inDevelopment ofPharmaceutical Products
10
solution, incorporating solubilising agents like surfactants, using a co-solvent, for-
mation of solid dispersion and turning the drug into a soluble complex(Volkova
et al. 2023; Pardhi and Jain 2021; Pardhi etal. 2024a,b). The right selection of
excipients to prevent drug-excipient or excipient-excipient interactions during for-
mulation, as well as the amount of the injectable solution, is another aspect that
must be considered. Therefore, developmentof parenteral dosage formsusing opti-
mized protocol, with the aim of creating a safe and effective treatment strategy as
well as a potential cure, is of utmost importance.
1.3.3 Oral Dosage Form
Oral solid dosage forms are used to achieve therapeutic effect in the mouth, throat,
digestive tract or for systemic actionfollowing oral or gastrointestinal absorption.
Drug and excipients can be milled, dried, encapsulated, blended, granulated or
tableted to provide oral solid dosage forms. Various oral solid dosage forms such as
tablets, capsules, lozenges, powders, granules, etc., have been widely used for deliv-
ering active pharmaceutical ingredients due to their convenience and consequent
patient compliance. Tablets, unit solid dosage forms administered to achieve imme-
diate drug release or modied release, are the most investigated oral solid dosage
form (Sohail Arshad etal. 2021). Since powder substances are typically used to
formulate solid dosage forms like tablets and capsules, a thorough characterisation
and understanding of the powder’s properties and effects on various manufacturing
processes are mandatory. This is because the properties of the powder not only
affect the manufacturing process but also the drug’s biopharmaceutical characteris-
tics, like the drug’s ability to dissolve in the gastrointestinal tract. The size and form
of the powder can affect the ow property of the powder, which is crucial for the
tableting process as an uneven ow might result in different tablet llings, which
can vary the content of the tablets. Other processes affected by the particle size and
shape are the mixing and the compaction processes (Vashishtetal. 2015).
Physical-mechanical characteristics of tablets, such as disintegration, porosity,
density, presence or absence of structural aws and viscoelastic qualities, affect the
performance of pharmaceutical formulations. Early and effective evaluation of
physical-mechanical properties of tablets during drug product development and
pharmaceutical production is very important. Furthermore, the USFDA established
quality by design, a scientic, risk-based framework to encourage creativity and
efciency in pharmaceutical research, manufacturing and quality assurance. To gain
a comprehensive understanding of the critical quality attributes of the completed
dosage forms, the USFDA released guidance on quality-by-design and process ana-
lytical technology tools. Most traditional characterisation techniques cause sample
invasiveness and only weakly demonstrate spatial mapping. Furthermore, these
methods offer ofine/at batch end monitoring, which is not very useful for making
subjective real-time operational modications. Novel noninvasive analytical tech-
niques have emerged because of relatively recent developments in software, tech-
nology, instrumentation and design, and they are presently being used to evaluate
tablets (Dave etal. 2017).
K. Jain etal.
11
1.3.4 Transdermal Dosage Form
Pharmaceutical formulations meant to be applied topically—either for systemic
therapy (transdermal formulation) or local treatment (topical formulation)—need to
have several variables carefully adjusted to ensure appropriate drug penetration and
achieve the intended result. The stratum corneum layer, which is the outermost layer
of the skin, is followed by the layers of epidermis and dermis and, lastly, the subcu-
taneous tissue. A barrier that stops foreign objects from penetrating the skin is the
stratum corneum. For the transdermal dosage form, drugs must rst enter the stra-
tum corneum and then should enter systemic circulation. The concentration of the
drug, its capacity to diffuse throughout the stratum corneum and its partition coef-
cient between the stratum corneum and its carrier are the primary determinants of
penetration into the stratum corneum. Biological parameters like age, sex and the
metabolic capacity of skin determine the absorption process across the skin.
Penetration enhancer, such as urea or phospholipids, can improve absorption by
increasing the capacity of drug to permeate the skin. Other enhancers include alco-
hols and alkanols (ethanol or decanol), terpenes, sulfoxides (dimethyl sulfoxide),
glycols, azones (laurocapram) and surfactants (Yang etal. 2024). The eld of trans-
dermal drug delivery system is experiencing continuous growth and development
due to the swift increase of essential knowledge that drives industrial development.
It is anticipated that as transdermal drug delivery technology advances, disease pre-
vention, diagnosis and control will improve, and as a result quality of patient life
would increase globally (Alkilani etal. 2015).
1.3.5 Inhalational Formulation
Inhalation of the therapeutic agents directly into the lungs is used to treat respiratory
tract illnesses including bronchitis and asthma. Inhalation dosage forms are crucial
in this regard, where the drug is delivered directly to the lung, hence minimising the
risk of systemic side effects associated with systemic drug administration. The med-
ication delivery mechanism or device is especially of signicant importance for
inhalational formulations and has a signicant inuence on the doctor’s choice and
the patient’s acceptance of a certain formulation.
Inhalational formulations are delivered via nebulisers, metered dose inhalers and
dry powder inhalers. Different criteria inuence the choice of inhalers; for example,
paediatric patientshave better compliance withnebulisers. The powder’s particle
size is a crucial component to consider when creating inhalational formulations, as
it inuences the powder’s ability to enter the respiratory tract and its potential to
reach the lung. Particles less than 5μm can enter the lung, whereas larger particles
are expelled from the respiratory tract. Generally, particles larger than 3μm are
needed to enter the alveoli, but it should be remembered that particles smaller than
1μm, for example, are typically exhaled from the respiratory system. Therefore, to
create a formulation with the required properties, particle size in inhalation formula-
tions is crucial and needs to be carefully tuned (Gibson 2005).
1 Advances inDevelopment ofPharmaceutical Products
12
1.3.6 Nasal Formulations
Both local and systemic treatments can be administered via the nasal route; the
former is crucial for treating a variety of nasal ailments, including rhinitis. Intranasal
dosage forms offer several advantages over other administration routes, such as
bypassing rst-pass metabolism, which is crucial for the drugs with low metabolic
stability, simple administration method and quick absorption. The nasal route of
administration can also be utilised to transport medications to the systemic circula-
tion. Nasal formulations require a proper choice of excipients, administration device
and avoidance of any incompatibilities. Other important factors include the selec-
tion of proper preservative in the formulation to prevent the microbial growth, i.e.
benzalkonium chloride is generally used as a preservative in nasal formulations. In
cases where a poor penetration is observed, such as with proteins or peptides, a
penetration enhancer may be used to increase the nasal absorption. Ensuring the
stability and compatibility of the substances utilised in the formulation is also cru-
cial (Amarji etal. 2018; Suthar etal. 2023; Sahu etal. 2024).
1.3.7 Ophthalmic Dosage Form
Different eye diseases are topically treated using ophthalmic formulations, as a sig-
nicant number of drugs can reach the site of action via administration of ophthal-
mic formulations into the eyes. Optimisation of ophthalmic formulations involves
the consideration of various factors like adjusting the pH and osmolarity of the
solution to ensure the drug’s solubility and the formulation’s sterility. There is a nar-
row range of permissible pH values that are close to the physiologic pH; in general,
the pH of the solution needs to be as close to the physiologic pH as possible. To
ensure that the solution is isotonic, the osmolarity of the solution must also be
adjusted to prevent irritation. The sterility of the ocular formulations is also of prime
importance; generally, preservatives are employed to inhibit microbial growth in the
ophthalmic dosage forms (Rowe etal. 2017).
The selection of preservative relies on formulation pH, presence of surfactant,
type of API/excipients, etc. Besides pH-adjusting agents, tonicity modiers, viscos-
ity modiers, buffers and preservatives are also used in the formulation of ophthal-
mic dosage forms. The viscosity modier prolongs the retention of drug on the
ocular surface, thereby increasing bioavailability. Certain formulations might con-
tain penetration enhancers and/or solubilisers such cremophor and polysorbates
(Zhang et al. 2022). These constituents enhance the molecule’s solubility in
aqueous media and could augment its penetration, thereby reducing the dosage
necessary to attain therapeutic efcacy and augmenting bioavailability (Amarji
etal. 2018).
K. Jain etal.
13
1.3.8 Stability Analysis ofPharmaceutical Products
In the early stage of the dosage form development, formulation and active drug
stability are assessed, where guidelines of the International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(ICH) or other present regulatory criteria are followed when conducting a stability
analysis. Understanding of environmental factors like temperature, moisture and
light, retesting intervals and storage settings, which affect shelf life, are of utmost
importance. Stability testing objectives vary depending on the stage of the drug
development and discovery process. The initial stage of product development seeks
to ascertain the drug’s inherent rigidity; potential interaction of excipients and drug;
and effect of acidity, alkalinity, humidity, oxygen and light on drug stability
(Chaurasia 2016). Data on the physicochemical stability of the pharmaceutical
product is obtained via accelerated stability analysis, which aids in determining the
most likely pathway for their breakdown. The determination of a stable formulation
is the main goal of preclinical research. Conrming the stability and data integrity
for the formulation batches is the purpose of stability testing in clinical trials (Smrity
etal. 2016).
The main goal of a stability study is to determine the variation in the quality of a
formulation over time under different environmental conditions. Stability study
comprises the determination of test parameters to determine the factors that can
inuence the potency, microbiological stability and physical stability of drugand
formulation. Physicochemical characteristics of active ingredients; presence of
excipients; process used to produce drug and its product; type of dosage form; pack-
aging used; exposure of drug to environmental factors during transportation, storage
and handling; and susceptibility of ingredients to oxidation, reduction, hydrolysis or
racemisation are just a few of the factors affecting the stability of the pharmaceuti-
cal product (Blessy etal. 2014).
To anticipate the possibility of potential degradation products, regulatory guide-
lines advise conducting forced degradation studies using acidic/alkali hydrolysis,
oxidation, thermolysis and photolysis. Nevertheless, none of the recommendations
provided precise instructions for the type, level, quantity or duration of stressors to
be used. Furthermore, a product’s stability testing technique may vary depending on
where in the world it is intended to be distributed or marketed. The ICH suggested
conditions for various climatic zones must be the basis for setting up circumstances
for real-time, long-term and rapid stability tests. A few unique specications can be
used to construct the stability testing technique for special products like phytophar-
maceuticals or biotechnological products. Therefore, while creating the protocol for
stability research, a wide range of relevant aspects must be considered (Sengupta
etal. 2018).
1 Advances inDevelopment ofPharmaceutical Products
14
1.4 Scale-Up Studies
All the industries, including the pharmaceutical industry, need to ensure that the
product is meeting all the quality attributes before commercialisation. It must be
noted that, unlike the other common products, pharmaceuticals must meet regula-
tory requirements during manufacturing as well before and aftermarketing of the
products (Raval etal. 2018). It is not advisable to manufacture products on a large
scale and proceed towards quality control in terms of economic aspects.
Pharmaceutical plants use pilot plant scale-up to establish an efcient manufactur-
ing method, so that commercial products can be produced on a large scale from a
lab scale formula. Pilot comprises the elements, material, man, method and machine,
which all contribute to the manufacturing process. Scale-up refers to the utilisation
of the information from a pilot plant model to make a prototype (Bandarapalle etal.
2024). Alternatively, it can be referred as the technology transfer from research to
the production unit to increase the production of a pharmaceutical product.
1.4.1 Pilot Plant
A pilot plant is dened as the process of developing a reliable, feasible manufactur-
ing process from a lab scale to a marketable product. A pilot plant is a small indus-
trial system that is run to provide data about the system’s behaviour for use in the
larger facility designed for large-scale production. It provide the necessary guide-
lines to make the manufacturing process sustainable, bringing more economic ben-
ets to the organisation. Pilot plant studies are used for formula standardisation,
evaluating various relevant processing equipment, and optimising and controlling
target production rates (Rane etal. 2023). It is a pre-commercial system that pro-
duces new pharmaceutical products on a small scale as on experimental aspects.
This batch of products is used to check the feasibility of large-scale manufacturing
and meet government regulatory requirements (Dhobale et al. 2018). The main
objectives of pilot plant studies are listed below:
• To identify the potential challenges and overcome those during the scale-up
• Production and process control guideline preparation
• To study the crucial elements of the process
• Preparation and supply of master manufacturing formula for manufacturing
• Evaluation and validation of process and equipment
• Evaluation of the formula to produce a stable batch
• To produce physically and chemically stable therapeutic dosage forms
• Review of the processing equipment
• To avoid the scale-up problems
• To try the process on a model of the proposed plant before committing a large
sum of money to a production unit
K. Jain etal.
15
These objectives are critical outcomes from a pilot plant and are very important
requirements for the efcient functioning.
1.4.1.1 Requirements foraPilot Plant Scale-Up
Before considering setting up a pilot plant, a few requirements are required to be met:
• The formula should be thoroughly veried to determine its ability to withstand
large-scale production.
• The correct identication of the processing equipment, which is most economi-
cal, simple and reliable in the production.
• Ensuring the availability of raw materials, which is required to produce the
product.
• Evaluation, validation and nalization of production and process controls.
• Provide necessary records and reports to support good manufacturing practices
(GMPs) and record of the formulation process, equipment utilised and specica-
tions (Kerone 2024).
1.4.2 Current Good Manufacturing Practices (cGMP)
In the healthcare industry, maintenance of high-quality standards is an important
factor, as it affects the safety and efcacy of medicines (Sharma etal. 2023). The
cGMP is an assortment of different policies, guidelines, codes and directives that
have been developed and issued by international organisations and institutions in
cooperation with the pharmaceutical industry and several national regulatory agen-
cies (Patel and Chotai 2008). The cGMP aims at the proper design, monitoring and
control of manufacturing processes and facilities. It mandates that pharmaceutical
manufacturers maintain appropriate control over their manufacturing processes,
ensuring the identity, strength, quality and purity of their products. It also provides
the essential guidelines for the production, distribution and supply of drugs, medical
devices and other healthcare products (Sharma etal. 2023; Gouveia etal. 2015).
The components of the cGMP can be summarised as described in Fig.1.2, which
includes quality control of nished product, quality control of packaging, written
procedure and other relevant documentation, manufacturing of premises with good
design, protective clothing, and properly designed and maintained equipment
(Shukla etal. 2016).
Implementation of cGMP in the production and testing practice ensures the qual-
ity of the product. cGMP guidelines should be followed by the quality assurance
(QA) system with the most care to achieve the goals (Shukla etal. 2016). The major
development of the GMP in association with the continuous efforts to make the
pharmaceutical manufacturing safer and more efcient is enlisted in Table1.1.
During the manufacturing process, there may be many instances where the pro-
duction must be regulated in accordance with the demand of the product as well as
the stability concerns of the product.
1 Advances inDevelopment ofPharmaceutical Products