The document discusses pharmaceutical excipients. It provides an overview of excipients, noting that drug products contain both active pharmaceutical ingredients and excipients. Excipients are chosen to ensure efficacious drug products with desired properties, a robust manufacturing process, consistency of drug release and bioavailability, and stability. Excipients are classified based on their functional roles. They must be manufactured and quality controlled according to good manufacturing practices and can impact drug product quality. International guidelines provide requirements for new excipients and limits on impurities and residual solvents.

1. Pharmaceutical Excipients
HOSSEN M. FARUK
B. Pharm (Hon's), MS Pharm Tech (UAP)
Executive Quality Assurance

2. Excipients – an overview
• Drug products contain both drug substance
(commonly referred to as active pharmaceutical
ingredient or API) and excipients. Formulation of API
with excipients is primarily to:
– Ensure an efficacious drug product with desired
properties and a robust manufacturing process
• The resultant biological, chemical and physical
properties of the drug product are directly affected by
the excipients chosen, their concentration and
interactions with the API:
–Consistency of drug release and bioavailability
–Stability including protection from degradation
–Ease of administration to the target patient
population(s) by the intended route

3. • Excipients are sub-divided into various functional
classifications, depending on the role that they are
intended to play in the resultant formulation.
• Certain excipients can have different functional roles in
different formulation types, e.g. lactose; widely
used as:
–a diluent, filler or bulking agent in tablets and
capsules
–a carrier for dry powder inhalation products (DPIs).
• Furthermore, individual excipients can have different
grades, types and sources depending on those
different functional roles….

4. Excipients

5. Excipient Manufacturing
• Subject to statutory requirements in section 510
(a) (2) (B) of the Food, Drug and Cosmetic Act
– Excipients must be manufactured, processed,
packaged and held in conformity with Current
Good Manufacturing Practice (CGMP)

6. Drug Excipient Quality
• Quality characteristics of excipients are significant to
the overall quality of the drug products in which they
are used
• Drug product manufacturers rely on excipient
manufacturers to provide excipients of uniform
quality, physical and chemical characteristics, e.g.,
levels of impurities

7. The pharmaceutical ingredients must be
stabilized toward:
• Environmental factors (air, water vapor,
sunlight)
• Interactions between different ingredients in
the drug or different functionalities in the
same molecule
• Manufacturing stress (sterilization,
compaction, etc.)

8. Pre-requisite terms………
• The commercial relevance of an excipient and therefore
the use of the excipient in at least one approved drug
product is a prerequisite for inclusion of a monograph
in the Ph.Eur., USP-NF, or JP/JPE.
• Both users and suppliers of excipients may request
their local pharmacopeia to develop a new monograph
once a material’s use in a commercial pharmaceutical
product has occurred.

9. • When there is no pharmacopoeia or other compendia
monograph, the manufacturer can establish its own
specification, based on an existing similar pharmacopoeia
monograph.
• An ingredient can be used in a pharmaceutical product as
an excipient even when there is no monograph for the
material in a compendium. Regulatory authorities require
a full safety and toxicological evaluation.
• Once a regulatory authority has approved a drug
application containing such an excipient, that excipient is
generally considered acceptable for the same route of
administration up to the same level of use providing the
same specifications are met as those used in the
previously approved drug.
Pre-requisite terms………

10. Excipient Monograph
Generally an excipient monograph contains the
following information:
• Monograph Name: The name by which the excipient will
be primarily found in the compendia.
• Official Title: The name by which the excipient is
generally known in industry.
• Definition: The acceptance criteria for the assay often
expressed as a percentage range.
• Packaging and Storage: Special packaging or storage
conditions necessary to protect the excipient.

11. • Labeling: Special requirements for labeling to
differentiate various grades of the excipient such as by
molecular weight or listing of additives present.
• Description: The excipient is characterized as to
chemical structure, molecular weight, physical form,
and solubility.
• Identification: There should be a test or tests that
confirm the identity of the excipient.
• Composition: There should be specific tests, where
possible, for concomitant and other components
especially for those above 0.1%. There should be tests,
where appropriate, for organic, inorganic and heavy
metal components as well as residual solvent(s).
Excipient Monograph

12. • Assay: There should be a test to quantify the excipient
content, where possible.
• Other tests: Where further characterization is needed,
other tests such as pH, preservative content, or
bacterial endotoxin should be recommended.
Exception* The European Medicines Agency (EMEA) also
requires for excipients not in the Ph.Eur.:
I) Physical Characteristics
II) Tests for parameters that may influence the
performance in the dosage form called functionality-
related characteristics.
Excipient Monograph

13. ICH Guidelines on Excipients
• The International Conference on Harmonisation (ICH) was
organized to develop uniform global requirements for
various technical aspects of pharmaceutical product
registration.
• ICH has approved guidance documents on the technical
requirements for drug products containing new
ingredients.
• While the focus is primarily on the dosage form and
active ingredients, several of the guidelines have an
impact on excipients and can affect the marketing of an
excipient.
• Excipient suppliers should familiarize themselves with the
following two documents as pharmaceutical customers
will expect to see compliance to these guidelines.

14. Q3A, Impurities in New Drug Substances
• ICH has issued the Q3A guideline for drug substances
which recommends steps for qualifying impurities in the
active pharmaceutical ingredient.
• Since such materials when found in excipients are often
beneficial to excipient performance, they are referred to
as other components.
• Other components which are potentially harmful or do
not contribute to the performance of the excipient are
identified and reported using the provisions of the
guideline.
• Where appropriate, consideration should be given to
establishing specification limits for certain other
components.

15. Q3A, Impurities in New Drug Substances
A composition profile is developed so that:
1. The potential for drug interactions with other
components can be determined by the user.
2. The impact on the composition can be assessed
following changes to:
o The Manufacturing Process
o Raw materials
o Packaging
The composition profile defines all components that
comprise the excipient.

16. Q3C, Impurities: Guideline for Residual Solvents
• ICH has also issued the Q3C guideline on residual
solvents which lists various organic solvents in one of
four classifications.
• They include – 1) solvents to be avoided, 2) solvents
to be limited, 3) solvents with low toxic potential, and
4) solvents for which no adequate toxicological data
was found.
• Therefore, in calculating the maximum allowable
residual solvent level in the excipient, the intended
use concentration of the excipient in the finished
dosage form along with other sources of the listed
solvent must be taken into account.

17. • Residual solvents should be limited as much as
possible in the excipients so that they are below those
listed in Q3C or are present only very low levels in the
drug product.
• This will then reduce or limit the need for routine
testing of residual solvents in the drug product, except
for those used in its manufacture.
• If the level of residual solvent exceeds those in the
Q3C guideline, the manufacturer should measure and
report the quantity of the residual solvent in each lot
of excipient.
Q3C, Impurities: Guideline for Residual Solvents

18. Tablets Excipients
• Excipients are chosen in tablet formulation to perform a variety of functions,
Like:
i) For providing essential manufacturing technology functions (binders, glidants,
lubricants may be added),
ii)For enhancing patient acceptance (flavors, colourants may be added),
iii)For providing aid in product identification (colourants may be added),
iv)For Optimizing or modifying drug release (disintegrants, hydrophilic polymers,
wetting agents, biodegradable polymers may be added),
v)For enhancing stability (antioxidant, UV absorbers may be added)

19. Excipients Function
Diluent Diluents make the required bulk of the tablet when
the drug dosage itself is inadequate to produce tablets
of adequate weight and size
Binder Binders are added to tablet formulations to add
cohesiveness to powders, thus providing the necessary
bonding to form granules, which under compaction
form a cohesive mass or a compact which is referred
to as a tablet.
Disintegrants A disintegrant is added to most tablet formulations to
facilitate a breakup or disintegration of the tablet
when placed in an aqueous environment.
TABLE. EXCIPIENT WITH THEIR FUNCTIONS IN TABLET
FORMULATION

20. Antifrictional Agents Function
Lubricant Lubricants are intended to reduce the friction
during tablet formation in a die and also during
ejection from die cavity.
Antiadherants Antiadherents are added to reduce sticking or
adhesion of any of the tablet granulation or
powder to the faces of the punches or to the die
wall
Glidants Glidants are intended to promote the flow of
tablet granulation or powder mixture from
hopper to the die cavity by reducing friction
between the particles.

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Excipients Function
Antioxidants Antioxidants are added to maintain product stability, they
act by being preferentially oxidized and gradually
c.onsumed over shelf life of the product
Chelating
agents
Chelating agents are added to protect against
autoxidation; they act by forming complexes with the
heavy metal ions which are often required to initiate
oxidative reactions.
Colours Colours are added to tablet formulation for following
purposes: to disguise off colour drugs, product
identification and for production of more elegant product.
Flavours Flavours are added to tablet formulation in order to make
them palatable enough in case of chewable tablet by
improving the taste.

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MISCELLANEOU
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Function
Wetting agent Wetting agents are added to tablet formulation to aid water
uptake during disintegration and assist drug dissolution.
Dissolution retardant Dissolution retardants as the name suggest, retards the
dissolution of active pharmaceutical ingredient(s).
Dissolution enhancer Dissolution enhancers as the name suggest, enhance the
dissolution rate of active pharmaceutical ingredient(s).
buffers Buffers are added to provide suitable micro environmental pH
to get improved stability and / or bioavailability.
Adsorbents Adsorbents are capable of retaining large quantities of liquids
without becoming wet; this property of absorbent allows many
oils, fluid extracts and eutectic melts to be incorporated into
tablets.

23. Enteric Coatings
Cellulose Acetate Phthalate (CAP)
• Tablets coated with enteric coatings will release their
contents in the small intestine, not the stomach.
• Such coatings are frequently used on products that my
irritate the stomach, such as aspirin.
• A commonly used coating material is cellulose acetate
phthalate (CAP)
Free carboxylic acid remains in
polymer.
This is an acidic functionality and is
deprotonated (ionized) at basic pH.

24. So, when [A-] = [HA], the pH = pKa.
The pKa of carboxylic acids is in the range of 3-5.
Thus carboxylic acids are protonated (nonionized) in the acidic
environment of the stomach [pH = 2], but ionized in the more
basic environment of the intestine [pH = 8].
Non-water soluble Water-soluble
ionic form

25. Thus the enteric coating becomes more water soluble
(since it is in the ionic form, usually more water soluble
than the nonionized form) in the intestine.

26. Disintegrants
Disintegrants are hydrophillic compounds that assist the break
up of granules, tablets, and capsules
The most widely used are carboxymethyl cellulose calcium (left)
and potato starch (right).

27. • During the compression process that is involved in
generating a tablet, the starch particles are deformed.
• This deformation is relieved upon wetting and hydration
of the starch, thus leading to breakup of the tablet.

28. Pharmaceutical applications of
Polymers
• Pharmaceutical excipients
• Drug delivery (Poly(lactide-co-glycolide)
(PLGA) microparticles
• Hydrogels
• Adhesive biomaterials

29. Pharmaceutical excipients
• Coat tablets: Microcrystalline cellulose (MCC), sodium
carboxylmethylcellulose (NaCMC), hydroxypropylmethycellulose
(HPMC), hydroxyethylcellulose (HEC), Hydroxypropylcellulose
(HPC), PEG, povidone
• Binder: acacia, gelatin, sodium alginate
• Disintegrants: Starch, carboxy methyl starch, povidone
• Plasticizer, PEG
• Thickening agents: xanthan gum (a natural gum
polysaccharide used as a food additive and rheology modifier )

30. Application of Poly Lactic Acid/ Poly Lactic-co-
Glycolic Acid polymers

31. What is Polymer Degradation?
 polymers were synthesized from glycolic acid in 1920s.
At that time, polymer degradation was viewed negatively as a
process where properties and performance deteriorated with
time.

32. Factors Influence the Degradation Behavior
 Chemical Structure and Chemical Composition
 Distribution of Repeat Units in Multimers
 Molecular Weight
 Polydispersity
 Presence of Low Mw Compounds (monomer, oligomers, solvents, plasticizers, etc)
 Presence of Ionic Groups
 Presence of Chain Defects
 Presence of Unexpected Units
 Configurational Structure
 Morphology (crystallinity, presence of microstructure, orientation and residue stress)
 Processing methods & Conditions
 Method of Sterilization
 Annealing
 Storage History
 Site of Implantation
 Absorbed Compounds
 Physiochemical Factors (shape, size)
 Mechanism of Hydrolysis (enzymes vs water)

33. Factors That Accelerate Polymer Degradation
 More hydrophilic backbone.
 More hydrophilic end groups.
 More reactive hydrolytic groups in the backbone.
 Less crystallinity.
 More porosity.
 Smaller device size.

34.  Morphological changes (swelling, deformation, bubbling,
disappearance…)
 Weight lose
 Thermal behavior changes
 Differential Scanning Calorimetry (DSC)
 Molecular weight changes
 Dilute solution viscosity
 Size exclusion chromatography(SEC)
 Gel permeation chromatography(GPC)
 Mass spectroscopy
 Change in chemistry
 Infared spectroscopy (IR)
 Nuclear Magnetic Resonance Spectroscopy (NMR)
Methods of Studying Polymer Degradation

35. Applications of Polymers
• Prolong drug availability if medicines are formulated
as hydrogels or microparticles.
• Favorably alter bio distribution, if formulated into
dense nanoparticles.
• Enable hydrophobic drug administration if formulated
as micelles.
• Transport a drug to its usually inaccessible site of
action if formulated as gene medicines.
• Make drugs available in response to stimuli

36. What is “PEGylation” ?
“PEGylation” is the covalent coupling of Non-Toxic,
Hydrophilic Poly ethylene glycol (PEG) to active
Pharmaceutical ingredients Such as Proteins , Peptides ,
colloids etc.
•More than 80 Poly Peptide Drugs are marketed in The
U.S and more than 350 Proteins and Peptides are
undergoing clinical trails right now.

37. PEG is not ready for conjugation
reactions by itself…..

38. Conjugation Chemistry…

39. How do the PEGs Work…
PEGylation increases the half-life of the biomolecule in the body via

40. In an aqueous medium, the long, chain-like PEG molecule is heavily hydrated and in
rapid motion. This rapid motion causes the PEG to sweep out a large volume and
prevents the approach and interference of other molecules. As a result, when
attached to a drug, PEG polymer chains can protect the drug molecules from
immune response and other clearance mechanisms, sustaining drug bioavailability .

41. Reducing Kidney Filtration
•PEGylation significantly increases the apparent size of the
conjugated drug compound

42. Pegfilgrastim = pegylated filgrastim
Pegfilgrastim
filgrastim
Polyethylenglycol (PEG)
18.800 Daltons Molecular weight 39.000 Daltons
Renal Primary pathway of elimination Via neutrophils
Daily Administration 1x / CT-cycle

43. In Protein Drug Delivery:
• PEGASYS: PEGylated alpha-interferons for use in the
treatment of chronic hepatitis C and hepatitis-B(Hoffman-La
Rochen)
•ADAGEN: received approval for the treatment of severe
combined immunodeficiency(SCID), a disease associated with
an inherited deficiency of adenosine deaminase36. Before the
availability
• PEG-Intron: PEGylated alpha-interferons for use in the
treatment of chronic hepatitis C and hepatit B(Schering-
Plough / Enzon)

44. Criteria for polymer selection
• The polymer should be soluble and easy to synthesis.
• It should have finite molecular weight.
• It should be compatible with biological environment.
• It should be biodegradable.
• It should provide good drug polymer linkage.

45. General Mechanism of drug release from polymer
1. Diffusion
2. Degradation
3. Swelling

46. 1.Diffusion
• Diffusion occurs when a drug or other active agent
passes through the polymer that forms the
controlled‐release device.
• Diffusion occurs when the drug passes from the
polymer matrix into the external environment.
• As the release continues its rate normally decreases
with this type of system since the active agent has a
progressively longer distance to travel and therefore
requires a longer diffusion time to release.
• In these systems, the combinations of polymer matrices
and bioactive agents chosen must allow for the drug to
diffuse through the pores or macromolecular structure
of the polymer upon introduction of the delivery system
into the biological environment without inducing any
change in the polymer itself.

47. 2.Degradation
• Biodegradable polymer degrades within the body as a
result of natural biological processes, eliminating the
need to remove a drug delivery system after release of the
active agent has been completed.
• Most biodegradable polymers are designed to degrade as
a result of hydrolysis of the polymer chains into
biologically acceptable and progressively smaller
compounds.
• For some degradable polymers, most notably the poly
anhydrides and poly ortho esters, the degradation occurs
only at the surface of the polymer, resulting in a release
rate that is proportional to the surface area of the drug
delivery system

48. 3. Swelling
• They are initially dry and when placed in the body will
absorb water or other body fluids and swell.
• The swelling increases the aqueous solvent content
within the formulation as well as the polymer mesh
size, enabling the drug to diffuse through the swollen
network into the external environment.

49. Biodegradable Polymers Used for Medical
Applications
 Natural polymers
 Fibrin
 Collagen
 Chitosan
 Gelatin
 Hyaluronan ...
 Synthetic polymers
 PLA, PGA, PLGA, PCL, Polyorthoesters …
 Poly(dioxanone)
 Poly(anhydrides)
 Poly(trimethylene carbonate)
 Polyphosphazenes ...

50. Degradation Schemes
 Surface erosion (poly(ortho)esters and polyanhydrides)
 Sample is eroded from the surface
 Mass loss is faster than the ingress of water into the
bulk
 Bulk degradation (PLA,PGA,PLGA, PCL)
 Degradation takes place throughout the whole of
the sample
 Ingress of water is faster than the rate of
degradation

51. Polymer Degradation by Erosion

52. Erodible Matrices or Micro/Nano spheres
(a) Bulk-eroding system
(b) Surface-eroding system