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Pharma Science Monitor 13(2), Apr-Jun 2022
THE TALE OF PHARMACEUTICAL EXCIPIENT SELECTION: FROM THE
LABORATORY TO THE INDUSTRIAL SCALE
Akshat D. Modi1,2*, Dharmeshkumar M. Modi3
1. Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada
2. Department of Genetics and Development, Krembil Research Institute, University Health Network, Toronto,
ON M5T 2S8, Canada
3. Gujarat Technological University, Ahmedabad, Gujarat 382424, India
Email id-akshat.modi@mail.utoronto.ca
ABSTRACT
Over the years, the selection of excipients that are key ingredients of the pharmaceutical
formulation has always been challenging tasks from a formulation scientist to the manufacturer.
Their inherent properties along with unique characteristics make them suitable for successful
dosage form globally. Various rules for selection at the laboratory scale with rock bottom criteria
for the number and concentration of excipients have been proposed in relation to the
pharmacological class of API. However, their compatibility, regulatory requirements and
manufacturer or supplier criteria are always under prospective consideration due to the
unavailability of harmonized guidelines. This review discusses these challenges in-depth and
suggests the novel steps to be followed during pre-formulation studies to industrial scale.
KEYWORDS: Pharmaceutical excipients; API-excipient compatibility; Excipient selection;
Supplier criteria; IPEC guidelines; Compendial excipients
1. EXCIPIENT - INACTIVE PHARMACOLOGICAL AGENT PLAYS AN ACTIVE
ROLE
The excipient, derived from the Latin word excipere, represents the broader class of every inert
pharmacological substance or a group of substances added intentionally in the formulation other
than the Active Pharmaceutical Ingredients (APIs) (Pifferi and Restani, 2003; Abrantes et al.,
2016; Singh et al., 2021; Singh and Chaudhary, 2016).
An active pharmaceutical ingredient (API) is a substance or mixture of substances in a finished
pharmaceutical dosage form, intended to provide desired pharmacological activity or use in the
PHARMA SCIENCE MONITOR
AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES
Journal home page: http://www.pharmasm.com
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diagnosis, cure, mitigation, treatment or prevention of disease or disorder or to influence the
structure or function of any part or organ of the body of human beings (Pifferi and Restani, 2003;
Haywood and Glass, 2011; Abrantes et al., 2016). The best API in the world is of not much value
without a suitable delivery system (Pifferi and Restani, 2003; Haywood and Glass, 2011).
The borderline between excipients and APIs is not clearly distinguished as well as some
excipients are also used as APIs (van der Merwe, 2020). For example, castor oil is an oily
vehicle, solvent, and plasticizer but it is also used as a laxative too; ascorbic acid and alpha-
tocopherol are used as antioxidants, but they are also used as vitamins (Pifferi and Restani,
2003).
Despite the type of dosage form suitable to be administered enterally, parenterally and topically,
the excipient tends to serve an essential role of supporting and delivering the APIs to the patient
by providing weight, volume and uniformity (Pifferi and Restani, 2003; Chaudhari and Patil,
2012; Amharar et al., 2016; Merkle, 2015). The addition of excipients ensures the stability,
precision and accuracy of the dose, improving the organoleptic characteristics as well as patients’
compliance (Pifferi and Restani, 2003; Abrantes et al., 2016). The excipients are not only key in
the manufacturing phase but also significant in controlling the release of APIs with the aim of
improving the bioavailability and subsequently the efficacy and tolerability of APIs (Pifferi and
Restani, 2003; Haywood and Glass, 2011; Wen et al., 2015).
Excipients can also contribute to the processing of drug delivery systems (Narang and Boddu,
2015; Hamman and Steenakamp, 2012). For instance, lubricants help in filling the die cavity
during compression, antioxidants protect the dosage form from oxidation, hardening agents
impart the shape to the suppositories, and sweetening agents modify the taste (Pifferi and
Restani, 2003).
Also, excipients aid in the recognition of the product’s identity and intensify the comprehensive
safety as well as the function of the formulation throughout the production process: during the
storage period, during and after its administration by the patient (Haywood and Glass, 2011;
Abrantes et al., 2016; Fathima et al., 2011).
2. ROLE OF EXCIPIENTS IN DOSAGE FORM
Today, APIs are available in various dosage forms like solid - tablets, capsules, powders,
granules, suppositories; liquid - solutions, suspensions, emulsions, elixirs; and semisolid -
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creams, gels, ointments (Haywood and Glass, 2011). Excipients utilised in various dosage forms
and their effects are shown in Table 1.
Pharmaceutical excipients are usually included in dosage forms in larger quantities than the API
and can make up to about 90% of the total mass/volume of medicinal products (van der Merwe
et al., 2020; Haywood and Glass, 2011). The excipient promises the desired physicochemical and
biopharmaceutical characteristics in the pharmaceutical dosage form (Serajuddin, 1999; Ratnam
et al., 2006).
The excipient is used as the carrier (vehicle or basis) or as a component of the carrier of APIs
(Zhang et al., 2018). The carrier consists of one or more excipients (Paudel et al., 2013). A
vehicle term is utilized for liquid preparations while a basic term is utilized for solid and
semisolid preparations (Fry, 1990).
The excipient performs one or manifold tasks, for example, Hydroxy Propyl Methyl Cellulose
(HPMC) can be used as a suspending agent, emulsifying agent, coating agent, binding agent, as
well as coating agent (Riberio et al., 2019; Rogers and Wallick, 2012).
The excipient performs its role and may or may not be present in the final preparation. For
instance, anhydrous ethanolic solution of polyvinylpyrrolidone is used as a binder for preparation
of granules (Luo et al., 2021; Darji et al, 2018). During the drying of granules, the ethanol is
vaporised, and it is removed from the dried granules (Abrantes et al., 2016).
The term “functional excipient” is used to describe an excipient that can provide an added
function or quality over and above the “conventional excipients” (Pifferi et al., 1999).
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Table 1. Excipients' roles in various dosage types
Excipient category
Role in dosage form
Tablets
Diluents/ fillers
Binders
Disintegrants
Glidants
Antiadherents
Colouring agents
Flavouring agents
Sweeteners
Coating polymer
- produce the bulk of the tablets
- bind the tablet powder ingredient together
- decrease disintegration time for faster release
- promote powder flow by reducing interparticle friction
- reduce adhesion between powder(granules)
- improve the appearance
- mask the unpleasant taste
- reduces the bitterness and improve the patient compliance
- produces film around the tablet to modify the release
Capsules
Shell material
Diluents/ fillers
Absorbents
Disintegrants
Plasticizers
Antidusting agents
Polymers
- to form the capsule body to fill the required material
- ensure regular flow of powder
- prevent degradation of hygroscopic material
- increase disintegration rate of filled content to up the
action
- imparts softness, elasticity, hardness to capsule shell
- prevent dusting that results from automatic capsuling
- control the rate of dissolution of drug
Liquid dosage forms
Vehicles
Buffers
Tonicity modifiers
Complexing agents
Surfactants
Suspending agents
Emulsifying agents
Colouring agents
Flavouring agents
Sweetening agents
Preservatives
- means of solubilizing different components
- control the pH and important in storage
- maintain tonicity with the body’s natural fluids
- binds reversibly with drugs to form stable complex
- increase solubility of the drugs and stabilise the system
- keep the insoluble particles in suspended form
- keep oil and water phases together
- impart colour to the formulation
- impart flavour to the formulation
- impart sweetness to the formulation
- preserve the formulation
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Semisolid dosage forms
Antioxidants
Humectants
Colouring agents
Flavouring agents
Preservatives
- protect from oxidation
- prevent the loss of moisture
- impart colour to the formulation
- impart flavour to the formulation
- prevent the growth of microorganisms
3. SELECTION OF EXCIPIENTS
The selection of the excipient(s) for a formulation should take into consideration the API
properties, process, type of formulation and potential impact on the formulation (Sjögren et al.,
2014; Leane et al., 2018). It is equally important to mention on the label the name of excipients
used in the preparation of dosage form as some people may be allergic to some ingredient or
religious purpose.
The selected excipient should be regulatory approved, safe, having desired quality and function
(Elder et al., 2016; Dickinson et al., 2008). Selection should be emphasised on type of dosage
form and route of administration. Numerous new excipients with enhanced physical, mechanical
and /or chemical properties have been synthesised and are available at times to get the desired
characteristics in the dosage form. The procedures to be followed in order to select required
characteristic excipients are shown in Figure 1.
Figure 1. Steps to be followed to select an excipient with the desired properties.
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3.1 Check the pharmacological category of API and excipients
The excipients included in the dosage form should not have any direct therapeutic action
(Haywood and Glass, 2011). Generally, an excipient should be pharmacologically inert but
sometimes it has its own effect in the body which may be similar or opposite to APIs (Zhang et
al., 2016). In the case of the same effect, it promotes synergism promoting a more pronounced
effect even at low drug dose. In contrast, the excipient with the antagonistic effect will make the
dosage form impractical leading to null effect of API.
For solid dosage form manufacturing of oral hypoglycemic agents, select excipients from the
category other than carbohydrate or lipid category (Okur et al., 2017). The care should be taken
not to use starch paste as a binder, cellulose compound as diluent or as a disintegrating agent.
These compounds in small amounts also play the opposite role in blood glucose level. As in this
point must be taken into consideration while narrowing down the list of excipients before
proceeding to check their compatibility studies during the preformulation stage.
3.2 Golden rules for selection of an excipient
As many companies are manufacturing the same dosage form for the same API but the success
of formulation lies in selection of excipients leading to knockout formulation. For achieving this
goal, the two golden rules are to be obeyed.
1. Always use the least number of excipients to prepare a dosage form
As we know that the excipient can serve as one or many functions in the formulation, the
excipient with the multiple roles helps not only in lowering the number of chemicals utilised but
reducing the chemical burden to the body as well (Setten et al., 2019).
Once it is followed, then:
2. Always use the lowest concentration or amount of the selected excipient
The selected excipient should be checked for varying amounts or concentration suitable for the
purposes to be served. The least one will be always preferred as it not only eliminates the higher
cost to the formulation and also exposes the body to slightest one (Marini et al., 2003).
3.3 API excipient compatibility studies
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The excipients sorted from above yardsticks must be compatible with APIs as well as other
excipients too, which could be achieved by compatibility studies. API excipient compatibility
studies constitute a vital stage in the formulation development. It is a promising approach for
acceptance or rejection of excipients, therefore permitting the quick optimization of dosage form
with desired characteristics like stability, bioavailability and manufacturability (Chadha and
Bhandari, 2014; Rowe et al., 2009).
Compatibility with the API to ensure that there is no undesired interaction between the API and
the excipient that could impact the stability and shelf life of the product (Chadha and Bhandari,
2014). The excipients combined with APIs are generally pharmacologically inert, but they can
interact with APIs physically or chemically or physiologically leading to unstable dosage form
due to formation of newer products (Chadha and Bhandari, 2014; Narang et al., 2009).
Physical interactions can result in change in dosage form uniformity, colour, odour, solubility etc
which may be advantageous or limiting (Chadha and Bhandari, 2014; Rowe et al., 2009).
Chemical interactions can lead to hydrolysis, oxidation, polymerization, racemization, photolysis
reactions are always harmful to the dosage form (Chadha and Bhandari, 2014; Rowe et al.,
2009). Physiological / biopharmaceutical interactions between dosage form and body fluids may
lead to variability in rate of absorption of the APIs. They include increase in gi motility,
dissolving the enteric film layer and decrease absorption of tetracycline antibiotics with Ca, Al,
Mg, Bi or Zn ions (Chadha and Bhandari, 2014).
So far, formulation scientists have been always looking for universal methods for checking API
excipient compatibility studies for years, but only some thermal and nonthermal techniques are
available due to differing physical and chemical nature of APIs and excipients as well as the
complex nature of interactions between them. These techniques overcome the disadvantages of
multiple sample preparation and long storage times of conventional compatibility testing
methods (Chadha and Bhandari, 2014). These techniques change with respect to their principles
of operation, sample size, duration of analysis, the type of stress i.e. thermal, mechanical etc
(Chadha and Bhandari, 2014; Rowe et al., 2009). Broadly these techniques are categorised into
thermal and nonthermal.
3.3.1 Thermal techniques
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Thermal techniques of analysis play a significant role in the screening of excipients for the first
stage of formulation development (Chadha and Bhandari, 2014). They comprise a group of
techniques in which the physicochemical properties of API are measured as a function of
temperature (Chadha and Bhandari, 2014. In this method, the test samples are subjected to a
controlled temperature over a given period of time (Chadha and Bhandari, 2014; Rowe et al.,
2009). This analysis plays an important role in identification of physicochemical incompatibility
between API and excipients. These techniques are differential scanning calorimetry, isothermal
microcalorimetry, and differential thermal analysis (Chadha and Bhandari, 2014; Rowe et al.,
2009).
Differential Scanning Calorimetry (DSC) is the leading thermal analysis technique used for years
together as it requires small sample size and gives rapid results (Mura et al., 1998). It is assumed
that the thermal properties (melting point, change in enthalpy, etc.) of API excipient mixtures are
the sum of the APIs and excipients if the components are compatible with one another (Chadha
et al., 2013). Incompatibility is identified by changes in appearance, shape, height, width of
endothermic or exothermic peaks, and/or variation in enthalpy curves (Malan et al., 1997).
Sometimes, the results are misleading if these thermal changes are very small. Also, it can’t
detect the incompatibilities occurring on a long term and results are to be confirmed with other
non-thermal methods (Chadha and Bhandari, 2014; Rowe et al., 2009; McDaid et al., 2003;
Botha and Lotter, 1990; Chadha et al., 2013; Mura et al., 1998).
Isothermal microcalorimetry (IMC) or isothermal stress testing is used to determine integrity of
pharmaceutical formulations. It measures the very small changes in amount of heat emitted or
absorbed by a sample (Verma and Garg, 2004). In this method, the samples are not heated and
don't require long storage times. So, it saves valuable time and effort during development of
formulation. The sample is placed in the calorimeter and the heat gained or emitted at a constant
temperature is monitored (Vueba et al., 2005). The significant change in the heat gained or
emitted indicates that the API and excipients are incompatible with one another (Chadha and
Bhandari, 2014; Rowe et al., 2009; Sims et al., 2003; Phipps and Mackin, 2000).
Differential Thermal Analysis (DTA) is used to identify and quantify the chemical composition
due to changes in the temperature between the sample and an inert reference under controlled
and identical conditions (Rowe et al., 2009). Here the absorption or emission of heat can be
compared with the reference. The incompatibility is identified by comparing DTA curves of API
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with API excipient mixture (Rowe et al., 2009). The change in the number, change in the pattern
of the peaks indicate the interaction between API and excipients.This method requires only
powder samples and temperature in the range of 200 to 500°C (Chadha and Bhandari, 2014;
Rowe et al., 2009).
3.3.2 Non thermal techniques
Vibrational spectroscopy techniques like Fourier Transform-IR(FTIR), Raman and near-Infrared
spectroscopy provide a unique fingerprint to the API and the excipients based on their physical
and chemical properties which makes them suitable to be used as a screening tool (Aigner et
al.,2011). The interaction between API and excipients will lead to change in the characteristics
peak due to polymorph transitions, dehydration, formation of hydrates/solvates as a result of
vibrational changes (Kogermann et al., 2007). Sometimes the overlapped peak in the spectra
makes it difficult to predict the interaction (Chadha and Bhandari, 2014; Rowe et al., 2009;
Stephenson et al., 2001; Blanco et al., 2006).
Powder X-Ray Diffraction (XRD) is used to characterise the crystalline nature of the materials.
Each crystalline material exhibits a unique x-ray diffraction pattern against a range of diffraction
angles (Weng et al., 2006). It will be useful in the evaluation of API polymorphic transitions.
Any interaction between API and excipient may lead to change in shift, appearance or
disappearance of the peak intensities (Chadha and Bhandari, 2014; Rowe et al., 2009; Weng et
al., 2006; Harding et al., 2008; Newman and Byrn, 2003).
Solid State NMR identifies the interactions between the API and the excipients through the
variations in the chemical shift occurring due to change in the electron density around the
interaction sites (Tishmack et al., 2003). This technique is useful due to higher selectivity,
limited interference from excipients and being able to detect polymorphic transitions if any
(Chadha and Bhandari, 2014; Rowe et al., 2009; Saindon et al., 1993; Tishmack et al., 2003).
3.3.3 Microscopic techniques
Scanning Electron Microscopy (SEM) characterises surface morphology of API and API
excipient mixture. If the interaction between the API and the excipients often results in
polymorphic transitions and changes in the crystal habits of the API, can be easily observed by
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studying the surface micrographs (Mura et al., 1998). It is used in combination with other
techniques like DSC (Chadha and Bhandari, 2014; Rowe et al., 2009).
3.3.4 Chromatographic techniques
These techniques are based on selective adsorption of components on a stationary phase (solid or
liquid with high surface area). As the API excipient mixture moves over the stationary phase, the
components are adsorbed and released at the different rates depending upon their affinities
towards the mobile phase (Chadha and Bhandari, 2014). The high resolution and detection power
with high accuracy, precision, specificity and sensitivity makes them suitable for identification of
incompatibility (Chadha and Bhandari, 2014; Rowe et al., 2009).
In Thin Layer Chromatography (TLC) method, the thin layer of adsorbent (silica, alumina) is
prepared on glass, plastic or metal plates which act as a stationary phase. The mixture of API and
the excipient (test sample) as well as individual API and excipient (control or reference) are
prepared in the suitable solvent/s which serve as a mobile phase (Rowe et al., 2009). The mobile
phase is run over the stationary phase in a controlled environment chamber. The distance
travelled by the analyte depends upon the comparative affinity for the stationary or the mobile
phase (Chadha and Bhandari, 2014). The distance is indicated by the retardation factor (Rf
value). If the Rf value is changed for a test with control or reference indicated the incompatibility
between API and excipient. This method is sturdy and cheap, making it versatile (Chadha and
Bhandari, 2014; Rowe et al., 2009).
In High Performance Liquid Chromatography (HPLC) method, a liquid mobile phase is pumped
under high pressure through the stationary phase (Liltrop et al., 2011). The separation of API
excipient mixture(sample mixture) based on adsorption, partition or ion exchange depending on
selected stationary phase is confirmed by the detector (Gu et al., 1990). High sensitivity,
accuracy, and wide applicability make it suitable even for determining API content with
predicting the quantitative change due to API excipient incompatibility (Chadha and Bhandari,
2014; Rowe et al., 2009; Malan et al., 1997; Liltrop et al., 2011; Gu et al., 1990).
3.4 Regulation considerations for selection of excipients
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Safety and quality are the key dual considerations for selecting the excipients (Pifferi et al.,
1999). The excipients vary depending upon the sources and grades which may affect the drug
product performance. The excipients are no longer considered inert substances because they may
interact with the API, lowering their efficacy (Goole et al., 2010).
They can produce unwanted impurities or modify ADME and lastly, decrease the availability of
API to required sites (Pindelska et al., 2017). The toxicity of excipients is not easy to justify due
to their large numbers from a variety of sources as well as possibility of secondary products and
contaminants (Abrantes et al., 2016). Although there are no day-to-day guidelines obtainable,
safety and quality can be attained by adopting and precisely following good manufacturing
practices (GMPs) (Ruban et al., 2018).
Excipient quality is described quite unusually into two groups: compendial and non-compendial
excipients. Compendial excipients are those for which a monograph exists. They meet specific
requirements given in the monograph and are manufactured under appropriate GMPs (Dave et
al., 2015).
Some excipients have more than one compendial monograph and are known as multi compendial
excipients. Compliance with compendial requirements is a legal and regulatory requirement as
per Pharmacopoeia of the respective regions. These excipients have consistent composition, lot
to lot and within lot too. GMP annexure 5 provides the guidelines for the manufacture of
pharmaceutical excipients. Non-compendial excipients do not have monographs but might also
be used in pharmaceutical formulations, which should be of supply grade (Osterberg et al.,
2011).
Some of the regulatory guidelines are in practice for a particular geometrical part while others
are applied to a particular class of chemical substances.
International Pharmaceutical Excipient Council (IPEC) is to encourage the international
harmonisation of different standards for manufacturing and use of excipients. It is a worldwide
association that advances quality in pharmaceutical excipients. The IPEC recommended the
guidelines for the safety assessment of excipients and GMP for bulk pharmaceutical excipients.
These guidelines give adequate information to characterise the safe state of use of excipients.
Conversely, they are used by excipient manufacturers to enable them to identify what customers
and regulators are looking for in a product. IPEC guidelines are available for different countries
like America, China, Europe, India, and Japan.
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Joint IPEC-PQG Good Manufacturing Practices Guideline document covers the quality
management system and the extent of GMP required for the manufacture of excipients intended
for use in drug products.
Generally Recognized As Safe Food Status (GRAS) refers under Federal Food, Drug, and
Cosmetic Act and states that any ingredient added to food must undergo evaluation for approval
by USFDA unless it’s a GRAS ingredient.
FDA’S Inactive Ingredient Guide (IIG) is prepared by DDIR (Division of Drug Information
Resources). It provides the information on “acceptable levels” of excipients approved in
pharmaceutical products. It can be qualified through the US Food and Drug Administration
(USFDA) approval mechanisms.
The nonclinical studies for the safety evaluation of pharmaceutical excipients are given by Food
and Drug Administration Centre for Drug Evaluation and Research (CDER) and Centre for
Biologics Evaluation and Research (CBER).
3.5 Select suitable supplier/manufacturer for selected excipient
Choosing the right excipient manufacturer and/or supplier can help to ensure the use of quality
excipients. Companies that manufacture, distribute and use excipients must meet appropriate
quality and regulatory requirements. The quality is expressed by various characteristics and are
used to assess the excipient suppliers.
The European Union Directive Guidelines on the Formalised Risk Assessment for Ascertaining
the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products of Human
Use provides the following characteristics for assessing the manufacture and supply of
excipients.
The ANSI excipient GMP standard highlights the following criteria to assess risk to protect an
excipient from contamination.
Hygienic practises: excipient contamination due to personal hygiene, illness, attire, unauthorised
access, food, medication, and tobacco.
Infrastructure, building: excipient contamination, cross-contamination, mix-ups.
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Infrastructure, equipment: excipient contamination due to material of construction, utilities,
water, process materials, and work environment (air handling, cleaning/sanitation, pest control
and drainage). In addition, self-certification or third-party certificates showing adherence to
GMP guidelines, many suppliers generate an excipient information package which includes key
information on quality, regulatory status, material specifications, change management,
physical/chemical attributes, and chemical composition. Therefore, for quality control indicators,
researchers should pay attention to selecting appropriate sources of supply and clarify the
specifications and models of excipients.
These following considerations are in addition to manufacturing the excipient in conformance to
excipient GMP:
1. Potential presence of transmissible spongiform encephalopathy (TSE)
Select the manufacturer which does not use the animal-derived raw materials. If not, please
ensure that an excipient is free from TSE. If the manufacturer uses one equipment for more than
one excipient production, he should ensure that there are no residues left by following proper
cleaning procedure to ensure free from TSE.
2. Potential for microbiological or endotoxin contamination
The microbial burden will come from water, air used for preparation of an excipient. Be sure that
the manufacturer uses water for injection of pharmacopeial grade. The air can be controlled and
monitored by using HEPA filters in case of sterile excipients.
3. Potential for the presence of impurities
The unwanted substances are added to the excipient from utilities, manufacturing sites and
processes. This can be minimised by controlling at each stage.
4. Supply chain complexity and security
Excipients are commonly sold through the distributor. The pharmaceutical company should
verify that the excipient lot has come from the excipient manufacturer.
5. Excipient stability
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Unless an excipient is affected by extremes of temperature, humidity, or exposure to oxygen, it is
of least concern about maintaining storage conditions.
6. Tamper-evident packaging
The excipient package openings should be protected with the tamper-evident seals unique to the
excipient manufacturer. The appearance of an authentic seal (or photo) should be provided by the
excipient manufacturer.
7. Labelling of excipient package
Typical excipient information packages should contain quality compliance, regulatory status of
excipients, manufacturing process information, site and supply chain security information, safety
statements (e.g. animal derived materials statement), technical information on functional
performance, stability information for transportation and storage. These considerations will help
to ensure the use of quality excipients in the manufacture of pharmaceuticals.
4. CONCLUSION
Pharmaceutical excipients are essential components of most modern dosage forms.
Pharmaceutical dosage forms contain ingredients other than the active drug that are essential for
their manufacture, stability, and function. These ingredients should be inert; however, they do
have the potential to cause adverse effects in sensitive individuals. Identifying such reactions and
finding the appropriate safety information will help to ensure a safe outcome for the patient. The
variability may originate from the source, the excipient-manufacturing process, or during the
manufacturing of dosage forms. Lot of time and effort is still needed in the field of excipients. In
pharmaceutical manufacturing, once profile of the API and excipient are known, and they are
found to be compatible, safe, legally permitted and sourcing from certified manufacturer or
vendor are the backbones along with formulation development leading to the success of the
branded product globally.
REFERENCES
1) Abrantes, C. G., Duarte, D. & Reis, C. P. An Overview of Pharmaceutical Excipients:
Safe or Not Safe? Journal of Pharmaceutical Sciences 105, 2019–2026 (2016).
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2) Aigner, Z. et al. Compatibility studies of aceclofenac with retard tablet excipients by
means of thermal and FT-IR spectroscopic methods. J Therm Anal Calorim 104, 265–271
(2011).
3) Amharar, Y. et al. Mitigating unwanted amorphisation: A screening method for the
selection of suitable excipients. European Journal of Pharmaceutical Sciences 81, 181–
188 (2016).
4) Blanco, M., Alcalá, M., González, J. M. & Torras, E. Near infrared spectroscopy in the
study of polymorphic transformations. Analytica Chimica Acta 567, 262–268 (2006).
5) Botha, S. A. & Lötter, A. P. Compatibility Study Between Naproxen and Tablet
Excipients Using Differential Scanning Calorimetry. Drug Development and Industrial
Pharmacy 16, 673–683 (1990).
6) Chadha, R., Arora, P., Garg, M., Bhandari, S. & Jain, D. S. Thermoanalytical and
spectroscopic studies on different crystal forms of nevirapine. J Therm Anal Calorim 111,
2133–2142 (2013).
7) Chadha, R. & Bhandari, S. Drug–excipient compatibility screening—Role of
thermoanalytical and spectroscopic techniques. Journal of Pharmaceutical and
Biomedical Analysis 87, 82–97 (2014).
8) Chaudhari, S. P. & Patil, P. S. Pharmaceutical Excipients: A review. INTERNATIONAL
JOURNAL OF ADVANCES IN PHARMACY, BIOLOGY AND CHEMISTRY 1, (2012).
9) Darji, M. A. et al. Excipient Stability in Oral Solid Dosage Forms: A Review. AAPS
PharmSciTech 19, 12–26 (2018).
10) Dave, V. S., Saoji, S. D., Raut, N. A. & Haware, R. V. Excipient Variability and Its
Impact on Dosage Form Functionality. Journal of Pharmaceutical Sciences 104, 906–915
(2015).
11) Dickinson, P. A. et al. Clinical Relevance of Dissolution Testing in Quality by Design.
AAPS J 10, 380–390 (2008).
12) Elder, D. P., Kuentz, M. & Holm, R. Pharmaceutical excipients — quality, regulatory and
biopharmaceutical considerations. European Journal of Pharmaceutical Sciences 87, 88–
99 (2016).
Impact factor: 0.3397/ICV: 4.10 ISSN: 0976-7908 16
Akshat et al. / Pharma Science Monitor 13(2), Apr-Jun 2022, 1-20
13) Fathima, N., Mamatha, T., Qureshi, H. K., Anitha, N. & Rao, J. V. Drug-excipient
interaction and its importance in dosage form development. Journal of applied
pharmaceutical science 1, 66–71 (2011).
14) Fry, W. R. Medical Perioperative Management. Arch Surg 125, 809 (1990).
15) Goole, J. et al. The effects of excipients on transporter mediated absorption. International
Journal of Pharmaceutics 393, 17–31 (2010).
16) Gu, L., Strickley, R. G., Chi, L. & Chowhan, Z. T. Drug-Excipient Incompatibility
Studies of the Dipeptide Angiotensin-Converting Enzyme Inhibitor, Moexipril
Hydrochloride: Dry Powder vs Wet Granulation. Pharmaceutical Research 07, 379–383
(1990).
17) Hamman, J. & Steenekamp, J. Excipients with specialized functions for effective drug
delivery. Expert Opinion on Drug Delivery 9, 219–230 (2012).
18) Handbook of pharmaceutical excipients: edited by Raymond C. Rowe, Paul J. Sheskey,
Marian E. Quinn. (APhA/Pharmaceutical Press, 2009).
19) Harding, L., Qi, S., Hill, G., Reading, M. & Craig, D. Q. M. The development of
microthermal analysis and photothermal microspectroscopy as novel approaches to drug–
excipient compatibility studies. International Journal of Pharmaceutics 354, 149–157
(2008).
20) Haywood, A. & Glass, B. D. Pharmaceutical excipients – where do we begin? Aust
Prescr 34, 112–114 (2011).
21) Kogermann, K. et al. Investigating Dehydration from Compacts Using Terahertz Pulsed,
Raman, and Near-Infrared Spectroscopy. Appl Spectrosc 61, 1265–1274 (2007).
22) Leane, M. et al. Manufacturing classification system in the real world: factors influencing
manufacturing process choices for filed commercial oral solid dosage formulations, case
studies from industry and considerations for continuous processing. Pharmaceutical
Development and Technology 23, 964–977 (2018).
23) Liltorp, K., Larsen, T. G., Willumsen, B. & Holm, R. Solid state compatibility studies
with tablet excipients using non thermal methods. Journal of Pharmaceutical and
Biomedical Analysis 55, 424–428 (2011).
24) Luo, Y., Hong, Y., Shen, L., Wu, F. & Lin, X. Multifunctional Role of
Polyvinylpyrrolidone in Pharmaceutical Formulations. AAPS PharmSciTech 22, 34
(2021).
Impact factor: 0.3397/ICV: 4.10 ISSN: 0976-7908 17
Akshat et al. / Pharma Science Monitor 13(2), Apr-Jun 2022, 1-20
25) Malan, C. E. P., de Villiers, M. M. & Lötter, A. P. Application of differential scanning
calorimetry and high performance liquid chromatography to determine the effects of
mixture composition and preparation during the evaluation of niclosamide-excipient
compatibility. Journal of Pharmaceutical and Biomedical Analysis 15, 549–557 (1997).
26) Marini, A. et al. Drug-excipient compatibility studies by physico-chemical techniques;
The case of Indomethacin. Journal of Thermal Analysis and Calorimetry 73, 529–545
(2003).
27) McDaid, F. M., Barker, S. A., Fitzpatrick, S., Petts, C. R. & Craig, D. Q. M. Further
investigations into the use of high sensitivity differential scanning calorimetry as a means
of predicting drug–excipient interactions. International Journal of Pharmaceutics 252,
235–240 (2003).
28) Merkle, H. P. Drug delivery’s quest for polymers: Where are the frontiers? European
Journal of Pharmaceutics and Biopharmaceutics 97, 293–303 (2015).
29) Mura, P., Faucci, M. T., Manderioli, A., Bramanti, G. & Ceccarelli, L. Compatibility
study between ibuproxam and pharmaceutical excipients using differential scanning
calorimetry, hot-stage microscopy and scanning electron microscopy. Journal of
Pharmaceutical and Biomedical Analysis 18, 151–163 (1998).
30) Narang, A. S. & Boddu, S. HS. Excipient Applications in Formulation Design and Drug
Delivery. in Excipient Applications in Formulation Design and Drug Delivery (eds.
Narang, A. S. & Boddu, S. H. S.) 1–10 (Springer International Publishing, 2015).
doi:10.1007/978-3-319-20206-8_1.
31) Narang, A. S., Rao, V. M. & Raghavan, K. S. Excipient Compatibility. in Developing
Solid Oral Dosage Forms 125–145 (Elsevier, 2009). doi:10.1016/B978-0-444-53242-
8.00006-0.
32) Newman, A. W. & Byrn, S. R. Solid-state analysis of the active pharmaceutical
ingredient in drug products. Drug Discovery Today 8, 898–905 (2003).
33) Okur, M. E., Karantas, I. D. & Siafaka, P. I. Diabetes Mellitus: A Review on
Pathophysiology, Current Status of Oral Pathophysiology, Current Status of Oral
Medications and Future Perspectives. actapharm 55, 61 (2017).
34) Osterberg, R. E., DeMerlis, C. C., Hobson, D. W. & McGovern, T. J. Trends in Excipient
Safety Evaluation. Int J Toxicol 30, 600–610 (2011).
Impact factor: 0.3397/ICV: 4.10 ISSN: 0976-7908 18
Akshat et al. / Pharma Science Monitor 13(2), Apr-Jun 2022, 1-20
35) Paudel, A., Worku, Z. A., Meeus, J., Guns, S. & Van den Mooter, G. Manufacturing of
solid dispersions of poorly water soluble drugs by spray drying: Formulation and process
considerations. International Journal of Pharmaceutics 453, 253–284 (2013).
36) Phipps, M. A. & Mackin, L. A. Application of isothermal microcalorimetry in solid state
drug development. Pharmaceutical Science & Technology Today 3, 9–17 (2000).
37) Pifferi, G., Santoro, P. & Pedrani, M. Quality and functionality of excipients. Il Farmaco
54, 1–14 (1999).
38) Pifferi, G. & Restani, P. The safety of pharmaceutical excipients. Il Farmaco 58, 541–
550 (2003).
39) Pindelska, E., Sokal, A. & Kolodziejski, W. Pharmaceutical cocrystals, salts and
polymorphs: Advanced characterization techniques. Advanced Drug Delivery Reviews
117, 111–146 (2017).
40) Ratnam, D. V., Ankola, D. D., Bhardwaj, V., Sahana, D. K. & Kumar, M. N. V. R. Role
of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. Journal of
Controlled Release 113, 189–207 (2006).
41) Ribeiro, D. et al. Polysaccharide-Based Formulations for Healing of Skin-Related Wound
Infections: Lessons from Animal Models and Clinical Trials. Biomolecules 10, 63 (2019).
42) Rodante, F., Vecchio, S., Catalani, G. & Tomassetti, M. Application of TA and Kinetic
Study to Compatibility and Stability Problems in Some Commercial Drugs. Journal of
Thermal Analysis and Calorimetry 66, 155–178 (2001).
43) Rogers, T. L. & Wallick, D. Reviewing the use of ethylcellulose, methylcellulose and
hypromellose in microencapsulation. Part 1: materials used to formulate microcapsules.
Drug Development and Industrial Pharmacy 38, 129–157 (2012).
44) Ruban, O., Pidpruzhnykov, Y. & Kolisnyk, T. Excipient risk assessment: possible
approaches to assessing the risk associated with excipient function. J. Pharm. Investig.
48, 421–429 (2018).
45) Saindon, P. J. et al. Solid-State Nuclear Magnetic Resonance (NMR) Spectra of
Pharmaceutical Dosage Forms. Pharmaceutical Research 10, 197–203 (1993).
46) Serajuddin, A. T. M. Solid dispersion of poorly water‐soluble drugs: Early promises,
subsequent problems, and recent breakthroughs. Journal of Pharmaceutical Sciences 88,
1058–1066 (1999).
47) Setten, R. L., Rossi, J. J. & Han, S. The current state and future directions of RNAi-based
therapeutics. Nat Rev Drug Discov 18, 421–446 (2019).
Impact factor: 0.3397/ICV: 4.10 ISSN: 0976-7908 19
Akshat et al. / Pharma Science Monitor 13(2), Apr-Jun 2022, 1-20
48) Sims, J. L. et al. A New Approach to Accelerated Drug-Excipient Compatibility Testing.
Pharmaceutical Development and Technology 8, 119–126 (2003).
49) Singh, A., Gupta, N. & Gupta, A. A REVIEW ON HERBAL EXCIPIENTS. Int J Indig
Herb Drug 05–08 (2021) doi:10.46956/ijihd.vi.111.
50) Singh, V. K. & Chaudhary, A. K. AYURVEDIC NATURAL EXCIPIENTS: AN
ADVANCE OPTION FOR MODERN MEDICAMENTS. IJPSR 7, (2016).
51) Sjögren, E. et al. In vivo methods for drug absorption – Comparative physiologies, model
selection, correlations with in vitro methods (IVIVC), and applications for
formulation/API/excipient characterization including food effects. European Journal of
Pharmaceutical Sciences 57, 99–151 (2014).
52) Stephenson, G. A., Forbes, R. A. & Reutzel-Edens, S. M. Characterization of the solid
state: quantitative issues. Advanced Drug Delivery Reviews 48, 67–90 (2001).
53) Tishmack, P. A., Bugay, D. E. & Byrn, S. R. Solid-State Nuclear Magnetic Resonance
Spectroscopy-Pharmaceutical Applications. Journal of Pharmaceutical Sciences 92, 441–
474 (2003).
54) van der Merwe, J., Steenekamp, J., Steyn, D. & Hamman, J. The Role of Functional
Excipients in Solid Oral Dosage Forms to Overcome Poor Drug Dissolution and
Bioavailability. Pharmaceutics 12, 393 (2020).
55) Verma, R. K. & Garg, S. Compatibility studies between isosorbide mononitrate and
selected excipients used in the development of extended release formulations. Journal of
Pharmaceutical and Biomedical Analysis 35, 449–458 (2004).
56) Vueba, M. L., Veiga, F., Sousa, J. J. & Pina, M. E. Compatibility Studies Between
Ibuprofen or Ketoprofen with Cellulose Ether Polymer Mixtures Using Thermal
Analysis. Drug Development and Industrial Pharmacy 31, 943–949 (2005).
57) Wen, H., Jung, H. & Li, X. Drug Delivery Approaches in Addressing Clinical
Pharmacology-Related Issues: Opportunities and Challenges. AAPS J 17, 1327–1340
(2015).
58) Weng, P.-J., Gao, G.-S., Ding, S.-X., Liang, X.-Y. & Tang, X.-R. The influence of pre-
core and BCP mutations on the severity of chronic hepatitis B. Zhonghua Gan Zang Bing
Za Zhi 14, 769–771 (2006).
59) Zhang, W. et al. The Effects of Pharmaceutical Excipients on Gastrointestinal Tract
Metabolic Enzymes and Transporters—an Update. AAPS J 18, 830–843 (2016).
Impact factor: 0.3397/ICV: 4.10 ISSN: 0976-7908 20
Akshat et al. / Pharma Science Monitor 13(2), Apr-Jun 2022, 1-20
60) Zhang, X., Xing, H., Zhao, Y. & Ma, Z. Pharmaceutical Dispersion Techniques for
Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs.
Pharmaceutics 10, 74 (2018).
