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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5441_Библиотеки_им_академика_М_И_Перельмана.pdf
77
to the composition of amino acid sequence variants, secondary or tertiary structure,
and posttranslational modications is essential in biotechnological product devel-
opment. Other important factors that contribute signicantly to the biological prop-
erties of the product include cell line screening, designing expression systems, and
process development. By applying QbD tools at the development stage, biotechno-
logical products can be optimized for their intended use, ensuring their safety, qual-
ity, and efcacy.
QbD and PAT are becoming increasingly important in the biotechnological
industry as they help to minimize failures in the nal product, improve process per-
formance, and reduce costs. Many companies such as Sandoz Pharmaceuticals and
Boehringer Ingelheim Pharma are implementing these concepts in their biotech
product development and process control. By using multivariate analysis tools and
spectroscopic tools, they can improve the quality of their products and reduce regu-
latory burden. Overall, QbD and PAT are important tools that can help the biotech-
nological industry to develop high-quality products more efciently and
cost-effectively.
3.10.5 QbD inAnalytical Method Development
In the analytical QbD approach, critical method attributes (CMA) and critical
method variables (CMV) are identied and varied systematically to optimize the
method. This helps in achieving the desired performance of the analytical method
and also helps in reducing the variability of the method. The use of a quality by
design approach in analytical method development can lead to a more efcient and
effective method, which can reduce the overall cost and time required for method
development and validation (Garg etal. 2015). Moreover, it also helps in meeting
the regulatory requirements and improving the quality of the nal product. Hence,
the analytical QbD approach has become an integral part of the analytical method
development process in the pharmaceutical industry. The ICH Q2 (R1) guidelines
provide the criteria for the method validation parameters such as linearity, accuracy,
precision, and repeatability. But these robustness parameters are analyzed at the
nal stage of the method development stage, during method validation, and this
eventually sometimes leads to undesired, inaccurate results. This necessitates entire
method development and validation repetition.
The ICH Q8 (R2) guidelines give space to method development and method vali-
dation in a systemic way which will help in developing the rugged and robust ana-
lytical method. Analytical QbD (AQbD) involves designing of analytical target
prole (ATP) and optimizing the design space for critical performance attributes by
varying critical method attributes and critical method variables. Nowadays, the ana-
lytical QbD approach is widely used in method development specically in HPLC
to increase robustness and ruggedness (Thakur etal. 2017).
By applying QbD principles in analytical method development, the quality of
analytical results can be improved while reducing the overall cost and time required
for method development and validation. This approach also helps to identify and
3 Optimization Techniques fortheDevelopment ofPharmaceutical Products
78
control the critical parameters that affect the performance of the analytical method,
leading to increased consistency and reliability of the results. Various applications
of QbD in the manufacturing of different dosage forms by using different pharma-
ceutical unit operations are summarized in Table3.1.
3.11 Conclusion
Quality by design (QbD) is a systematic approach that emphasizes product and
process understanding, based on sound science and quality risk management. The
use of QbD in the pharmaceutical industry has the potential to enhance perfor-
mance, offer regulatory relief and adaptability, and bring about signicant nancial
gains throughout the product life cycle. Formulation by design (FbD) is a key part
of QbD and is being extensively investigated by budding scientists for better know-
how of the product and process development for an unequivocal universal accep-
tance. QbD and FbD techniques are being increasingly used in the development of
pharmaceutical products, biotechnological products, and new chemical entities,
leading to the ling of various new drug applications and abbreviated new drug
applications. The QbD approach provides a greater understanding of the process
and the result, which helps in the development of higher-quality products. However,
the implementation of QbD and FbD approaches faces several challenges that need
to be addressed. Overall, the emergence of QbD and FbD as quality tools, their
applications in different elds, and various regulatory guidelines have revolution-
ized the pharmaceutical industry and improved the safety and efcacy of nished
products.
Acknowledgments We are highly thankful for nancial support obtained from ICMR-SRF to
Miss Shivani Saraf, Mr. Pritish K. Panda, Mrs. Pooja Das Bidla, and Miss Sarjana Raikwar.
Authors report no potential conict of interest.
Declaration of Competing Interests
The authors declare no competing interests.
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4
Pharmaceutical Product Development:
Formulation Additives
MeenakshiPatel, DhruviPatel, HitarthiMayurPatel,
andLalitLataJha
Abstract
This chapter offers a complete assessment of the key role played by formulation
additives in the development of pharmaceutical dosage forms. Beginning with an
insightful introduction to formulation additives, the chapter emphasises on their
signicance in achieving desired product characteristics. A systematic break-
down follows, categorising formulation additives based on the types of dosage
forms and providing detailed insights into the additives used in each category,
shedding light on their functions and applications. The importance of under-
standing drug-additive interactions during formulation development has also
been discussed, covering physical, chemical and therapeutic incompatibilities,
along with analytical techniques to characterise such interactions. Recent
advances in additive science, such as functional and co-processed additives and
novel materials, are also explored along with international patented excipients.
Additionally, the chapter provides insights into related regulatory perspectives,
including generally recognised as safe (GRAS), international impurity guide-
lines (IIG) and International Pharmaceutical Excipients Council (IPEC), to
ensure compliance and safety in pharmaceutical formulations. This chapter
serves as a necessary source for those engaged in pharmaceutical product devel-
M. Patel (*)
Department of Pharmaceutics, School of Pharmacy, Faculty of Pharmacy, Parul University,
Vadodara, Gujarat, India
D. Patel
Department of Pharmaceutics, Parul Institute of Pharmacy & Research, Faculty of Pharmacy,
Parul University, Vadodara, Gujarat, India
H. M. Patel · L. L. Jha
Department of Pharmaceutics, School of Pharmacy, Faculty of Pharmacy, Parul University,
Vadodara, Gujarat, India
84
opment, providing a comprehensive and up-to-date perspective on formulation
additives.
Keywords
Formulation additives · Excipients · Drug-excipient compatibility · Co-processed
additives
4.1 Introduction toFormulation Additives
Formulation additives in pharmaceuticals refer to the substances that are added dur-
ing the manufacturing process to enhance the physical properties, stability or per-
formance of the nal product. They are pharmacologically inactive organic or
inorganic substances obtained from natural, semisynthetic or synthetic source. The
selection and quantity of additives incorporated into the formulation depends on the
characteristics of drug, type of formulation and route of administration. The addi-
tives chosen for the preparation of any kind of dosage form affect the safety, efcacy
and pharmacokinetics of the drug and also decide the formulation aspects of the
whole formulation development process.
Additives like binders, llers, disintegrants and lubricants assist in the manufac-
turing of tablets and capsules, ensuring their physical integrity and facilitating
proper dissolution in the body. Similarly, solubilisers, surfactants and complexing
agents aid in enhancing the solubility of poorly soluble drugs, thereby improving
their absorption and therapeutic efcacy. Additionally, preservatives, antioxidants
and stabilisers play a crucial role in preventing degradation and maintaining the
potency of medications throughout their shelf life. The careful selection and precise
integration of these formulation additives are critical in ensuring the safety, efcacy
and quality of pharmaceutical products that ultimately benet patients worldwide.
Initially considered as inert substances, additives were ignored in safety evalua-
tions due to the belief that they remained inactive within formulations. However,
this assumption has changed with time as research has unveiled their active roles
and deep impact on the safety and efcacy of medicinal substances. Additives can
exhibit physical, chemical and biopharmaceutical interaction with drugs. The vari-
ous examples in the past have proved that overlooking the safety evaluation of these
additives could compromise the overall safety prole of medications. The devastat-
ing 1937 sulphanilamide incident, which led to the tragic deaths of numerous chil-
dren, happened due to the presence of diethylene glycol as solvent in the formulation
(Ballentine 1981). This incidence urged the enactment of the Federal Food, Drug,
and Cosmetic Act of 1938, leading to transformation in regulatory frameworks. It
highlighted the necessity of strict testing and evaluation, recognising that these sub-
stances could interact with the body, the drug itself or other additives, ultimately
precipitating the toxicity and diminishing the drug efcacy. This chapter shows the
signicance of formulation additives, explaining their impact on product develop-
ment, from enhancing bioavailability to ensuring optimum drug delivery systems
including the regulatory aspects.
M. Patel etal.
85
4.2 Importance ofAdditives inDevelopment
ofPharmaceutical Dosage Form
Additives are considered as essential constituents without whom the preparation of
pharmaceutical dosage forms would be virtually impossible. Their importance
ranges from improving the physical appearance to controlling the release prole of
drug from the formulation. Rather than just being an inactive support, additives now
play a more important role as they also aid in delivering, safeguarding, stabilising,
noticing, elevating and improving patient compliance as well as elegance. Not only
the additive but their variability in terms of grade also has a deep impact on the
functionality of dosage form (Dave etal. 2015; Zarmpi etal. 2017). “Functionality”
refers to the necessary activity of the specied additive, which in other words is an
intrinsic quality of the additive in the pharmaceutical formulation (Narang etal.
2017). This functionality is determined by the technique, type and rate of incorpora-
tion of the additive in the dosage form.
Additives are added in the formulation according to their properties, to preserve
physiochemical property of drug substance and dosage form. Figure4.1 shows the
ideal properties of additives used in the development of pharmaceutical formula-
tion. The importance of ideal properties in formulation additives lies in their ability
to optimise drug delivery, ensure product quality and facilitate efcient manufactur-
ing while prioritising patient safety and therapeutic efcacy.
Studies have proved that choosing a right type of additive is essential for ensur-
ing the stability of the formulation (Veronica etal. 2022). One of the primary roles
of additives lies in their ability to provide structural integrity and stability to dosage
forms. These components, ranging from binders, llers and disintegrants to preser-
vatives and stabilisers, form the backbone of formulations, ensuring the stability,
cohesiveness and robustness of tablets and capsules. Beyond the physical
Fig. 4.1 Ideal properties of pharmaceutical formulation additives
4 Pharmaceutical Product Development: Formulation Additives
86
construction, additives contribute signicantly to the functionality and performance
of pharmaceutical formulations (Bodratti and Alexandridis 2018). Additives such as
solubilisers, surfactants and complexing agents play a signicant role in enhancing
the solubility of poorly soluble drugs, thereby improving their absorption and thera-
peutic efcacy (Vadlamudi and Dhanaraj 2017). They inuence the release kinetics,
ensuring controlled and sustained delivery of medications to achieve desired thera-
peutic outcomes while minimising adverse effects (Rosiaux etal. 2014). This indi-
cates that additives not only inuence the physical appearance but also affect the
dissolution rates, bioavailability and pharmacokinetics of active pharmaceutical
ingredients (API) (Li etal. 2023). They may be added in the formulation to improve
the drug solubility and permeability consequently increasing the bioavailability
(Panakanti and Narang 2015). Additionally, these additives might be introduced to
prolong shelf life, maintain consistent product quality or streamline the manufactur-
ing process itself. Additionally, these additives are also necessary to guard against
microbial contamination and formulation deterioration (Kusuma et al. 2020).
Furthermore, additives contribute to the enhancement of patient compliance by
inuencing various attributes of the formulation such as taste, appearance and ease
of administration (Adamkiewicz and Szeleszczuk 2023; Malaquias etal. 2018).
Masking unpleasant tastes, improving palatability and ensuring good visual appear-
ance of the formulation ensure the patient acceptability and adherence to prescribed
regimens, hence achieving better treatment of the disease or disorder.
While using the additives in the preparation of dosage form, a thorough under-
standing of additive science is required to prevent any formulation errors. The addi-
tive used in the formulation needs to be compatible both chemically and physically
with the active pharmaceutical ingredient and the other ingredients, including the
packing material (Abrantes etal. 2016). Therefore, evaluation of drug and additives
is required, along with choosing the concurrent use and potential contradiction.
Additionally, conventional additives need to be innovated in additives are required
to t in them as per the use of the formulation. There is a gap in the additive design
and discovery eld because existing additives are frequently combined in different
ratios to change their action. They can be categorised based on various criteria such
as their use, chemical composition, route of administration, etc., for understanding
their roles and applications in drug formulations (Fig.4.2).
4.3 Types ofFormulation Additives
4.3.1 Additives forOral Solid Dosage Forms
The most widely used types of oral solid medication products are various kinds of
tablets and capsules. Generally, capsules and tablets are solid dosage forms with a
fairly long shelf life that release the API immediately if its release rate is not pur-
posefully changed. The modied release dosage solid oral dosage forms are gener-
ally prepared to sustain the release of drug. In order to attain desired dosage form
parameters like drug content, hardness or crushing strength, disintegration time,
M. Patel etal.
87
friability, tensile strength and dissolution time, polymeric additives are combined
with an API and processed using various methods. Primarily, they aid in ensuring
the stability and uniformity of the dosage form throughout its shelf life, preventing
degradation and maintaining the drug’s efcacy. Additives also contribute to enhanc-
ing the physical characteristics of the formulation, such as improving ow proper-
ties, compressibility and dissolution rates. Additionally, they assist in masking
unpleasant tastes, controlling the release prole of the drug and facilitating easier
manufacturing processes. Moreover, certain additives act as llers, binders, disinte-
grants or lubricants, optimising the formulation’s performance and ensuring consis-
tent drug delivery to the patient (Fig.4.3). The strategic incorporation of additives
is essential to guarantee the quality, safety and effectiveness of oral solid dos-
age forms.
Various additives utilised in solid dosage form are as follows:
4.3.1.1 Fillers/Diluents
These additives add bulk to the formulation, facilitating the handling and manufac-
turing processes when the dose is small. Examples include lactose, mannitol, micro-
crystalline cellulose, calcium phosphates, sorbitol, sucrose, hydrolysed starch,
immediately compressible starch and various cellulose derivatives.
4.3.1.2 Binders
Added at a certain point in wet granulation, these can be liquid or dry powders that
help to form granules or give cohesive force between particles during direct com-
pression for mechanical strength. Binders such as starch, cellulose derivatives (like
Fig. 4.2 Various criteria for classifying additives
4 Pharmaceutical Product Development: Formulation Additives