Advanced Drug Delivery System-Practical Note

Mansoura University
Faculty of Pharmacy
Department of Pharmaceutics
Pharm D – Program
Level Five - Pharmacy Students
Practical Notes in
Advanced drug delivery systems (PT 5211) Level Five Pharm D- Pharmacy Program
Introduction
The course aims to provide students with insights and competencies related to the
principles of pharmaceutical pre-formulation as a gateway to dosage forms design
and formulation. Emphasis is placed on developing formulations based on the
physical and chemical properties of the drug substance and the intended use of the
drug product.
The course also introduces the students to the formulation principles and applications
of novel and targeted drug delivery systems by transforming proteins, genes, and
other biotechnology driven compounds into therapeutic products. In addition to
formulation aspects of biotechnology derived pharmaceuticals, it also covers the
application of polymers and excipients to solve problems/issues concerning the
optimization of absorption, selective transport, and targeting.
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((Pharm D( – ‫بكالوريوس الصيدلة ( فارم دى‬

Course Specification
Academic year: 2023/2024
Course name: Advanced Drug Delivery ‫ أنظمة توصيل دواء متقدمة‬:‫اسم المقرر‬
Systems
Academic Level: Level 5 ‫ الخامس‬: ‫المستوى األكاديمي‬
Scientific department: Pharmaceutics ‫ الصيدالنيات‬: ‫القسم العلمي‬
Head of Department: : ‫رئيس القسم‬

Prof. Dr. Irhan Ibrahim Abu Hashim ‫ أرهان ابراهيم ابو هاشم‬/‫د‬.‫ا‬
Course Coordinator: : ‫منسق المقرر‬

Prof. Dr. Marwa Salah El-Din El-Dahhan ‫ مروه صالح الدين الدهان‬/‫د‬.‫ا‬
University Mansoura
Faculty Pharmacy
Department offering the course Pharmaceutics
Department supervising the course Pharmaceutics
Program on which the course is given B. Pharm. (Pharm D)
Academic Level Level 5, Second semester, 2023/2024
Date of course specification approval September 2023
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A. Basic Information: Course data:
Course Title Advanced Drug Delivery Systems

Course Code PT 5211
Prerequisite ------
Teaching credit Hours: Lecture 1
: Practical 1
Total Credit Hours 2
B. Professional Information:
1. Course Aims:
This course enables the students to:
● Gain comprehensive knowledge of the principles of pharmaceutical pre-formulation as a
gateway to dosage forms design and formulation.
● Explain formulations based on the physical and chemical properties of the drug substance
and the intended use of the drug product.
● Illustrate the formulation principles and applications of novel and targeted drug delivery
systems by transforming proteins, genes, and other biotechnology driven compounds into
therapeutic products.
● Know the formulation aspects of biotechnology derived pharmaceuticals.
● Explain the application of polymers and excipients to solve problems/issues concerning
the optimization of absorption, selective transport, and targeting.
3
2. Course k. elements:
Upon completing the course, the student will be able to dominate the following key elements
Domain 1- fundamental knowledge
Program K. Course K.
Course K. element
element no. element no.
1.1.1 1.1.1.1 Define the principles of pre-formulation.
1.1.1.2 Explain the basis for the development of strategies to deliver therapeutic
agents to specific target sites at rates appropriate for the optimization of
therapeutics effect.
1.1.3 1.1.3.1 Define the types, characteristics, and formulation methods of the
advanced drug delivery systems using different polymers.
1.1.3.2 Classify different techniques for the preparation of different advanced
drug delivery systems and their relevant basic principles, advantages, and
disadvantages of each technique.
Domain 2: professional and ethical practice

Course K. element
2.2.4 2.2.4.1 Use different techniques needed for the development, formulation, and
evaluation of advanced drug delivery systems using different polymers.
2.2.4.2 Classify the modern systems in the development of new trends to deliver
drug molecules to specific target sites.
Domain 4: personal practice:

Course K. element
4.1.2 4.1.2.1 Retrieve and evaluate the information and work effectively in a team.
4.3.2 4.3.2.1 Practice independent learning to promote continuous professional
development.
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3. Course Contents:
Week No. Topics Lecture
credit Hours
1 Introduction of pre-formulation. 1
2 Physical properties of the drugs and their effects on pre-formulation. 1
3 Stability and chemical properties of the drugs and their effects on pre- 1
formulation.
4 Targeted drug delivery (introduction, general concepts). 1
5 Mechanisms of targeting and strategies 1
6 Targeted Drug Delivery Strategies 1
7 Nano-sized drug delivery systems (introduction, advantages). 1
8 Nano-sized drug delivery systems (types). 1
9 Functionalization of nanocarriers and drug loading in nanocarriers. 1
(Self-learning topic: liposomes, solid lipid nanoparticles).
10 Implants: introductions, advantages and applications. 1
11 Polymers (natural polymers) 1
12 Polymers (synthetic polymers) 1
13 Biotechnology therapeutic products 1
14 Gene therapy medicinal products and applications 1
15 Compensatory and alternative lecture 1
16 Revision and quiz 1
17 Final Written And Oral Exam -
Week No. Practical topics Practical
credit hours
1 Pre-formulation (Physical properties of the drugs). 1
2 Pre-formulation (Solubility and chemical properties of the drugs) 1
3 Targeted drug delivery (Main mechanisms of targeting) 1
4 Targeted Drug Delivery Strategies 1
5 Nano-sized drug delivery systems: Techniques for nanoparticles 1
preparation (Solid lipid nanocarriers, liposomes)
6 Nanocarriers‑strategies of the targeting mechanism 1
7 Conventional nanoparticles preparation techniques 1
8 Midterm exam -
9 Characterization Techniques of nanocarriers (part 1) 1
10 Characterization Techniques of nanocarriers (part 2) 1
11 Implants: applications of implantable drug delivery systems. 1
12 Polymers: applications of polymers 1
13 Biotechnology therapeutic products: Formulation Considerations of 1
Biopharmaceutical
14 Stability of Protein Based Pharmaceuticals 1
15 Revision and activity 1
16 Practical Exam 1
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4. Teaching and Learning Methods:

No Teaching and learning Methods Weeks K. elements to be
addressed
4.1 Computer aided learning: 1.1.1.1, 1.1.1.2,
a. Lectures using Data show, power Point presentations 1-16 1.1.3.1, 1.1.3.2,
b. Hybrid learning 2.2.4.1, 2.2.4.2,
● Online learning through my mans "Mansoura
university" .
● Online learning through my mans "Mansoura
university" as recorded video of practical session
● Interactive discussion through My Mans.
4.2 Advanced lecture (Group discussion ) 1-16 1.1.1.1, 1.1.1.2,
1.1.3.1, 1.1.3.2,
2.2.4.1, 2.2.4.2,
4.1.2.1
4.3 Practical works and tutorials 1-16 1.1.1.1,
1.1.1.2, 1.1.3.1,
1.1.3.2, 2.2.4.1,
2.2.4.2, 4.1.2.1
4.4 Self-learning 9 4.1.2.1, 4.3.2.1
4.5 Collaborative learning: Research Project 9, 10, 1.1.3.1, 1.1.3.2,
11 4.1.2.1
5. Student Assessment:
a- Assessment Methods:
1-Periodical (Mid-term exam) / Course work 1.1.1.1/ 1.1.1.2 / 2.2.4.2
2-Practical exam using OSPE 1.1.1.1 / 1.1.1.2 / 1.1.3.1 / 1.1.3.2 / 2.2.4.1 / 2.2.4.2
3-Written exam 1.1.1.1 / 1.1.1.2 / 1.1.3.1 / 1.1.3.2 / 2.2.4.1 / 2.2.4.2
4-Oral 1.1.1.1 / 1.1.1.2 / 1.1.3.1 / 1.1.3.2 / 2.2.4.1 / 2.2.4.2 /
4.1.2.1 /4.3.2.1
b- Assessment schedule
Assessment 1 Periodical (Mid-term 7-9th week
exam)/Course work
Assessment 2 Practical applying OSPE 16 th week
Assessment 3 Written Start from 17th week
Assessment 4 Oral Start from 17th week
Other assessment
c. Weighing of assessments
1 Periodical (Mid-term exam)/Course work 15%
2 Practical examination & tutorial 25%
3 Final-term examination 50%
4 Oral examination 10%
Total 100%
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6. Facilities required for teaching and learning

Classroom Data show- Computers, sound system-Internet, Platform
Laboratory facilities Data show, computers, white board
Library Books and Pharmacopoeia
7. List of References
No Reference Type
1. Electronic book “Advanced Drug Delivery Systems” prepared by staff eBook
members.
2. Essential
Mitra A, Lee CH, Cheng K. Advanced Drug Delivery. Wiley; 2013
textbook
3. Mozafari M. Nanoengineered Biomaterials for Advanced Drug Delivery. Recommend
Elsevier; 2020. ed textbook
4. Dua K, Mehta M, Pinto T de JA, Pont LG, Williams KA, Rathbone M. Recommend
Advanced Drug Delivery Systems in the Management of Cancer. Elsevier; ed textbook
2021.
5. http://www.sciencedirect.com / http://www.google.com / Websites
http://www.pubmed.com
https://www.ekb.eg
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8. Matrix of knowledge and skills of the course

A) Theoretical part:
Course contents / Domain 1 Domain 2 Domain 4
K. elements 1.1.1.1 1.1.1.2 1.1.3.1 1.1.3.2 2.2.4.1 2.2.4.2 4.1.2.1 4.3.2.1
Introduction of pre-formulation. ✔ ✔
Physical properties of the drugs and their effects on pre-
✔ ✔
formulation.
Stability and chemical properties of the drugs and their effects on
✔ ✔
pre-formulation.
Targeted drug delivery (introduction, general concepts). ✔ ✔
Mechanisms of targeting and strategies ✔ ✔

Targeted Drug Delivery Strategies ✔ ✔ ✔
Nano-sized drug delivery systems (introduction, advantages). ✔ ✔ ✔ ✔
Nano-sized drug delivery systems (types). ✔ ✔ ✔
Functionalization of nanocarriers and drug loading in ✔
nanocarriers. ✔ ✔ ✔ ✔
(Self-learning topic: liposomes, solid lipid nanoparticles).
Implants: introductions, advantages and applications. ✔ ✔ ✔ ✔ ✔
Polymers (natural polymers) ✔ ✔ ✔ ✔
Polymers (synthetic polymers) ✔ ✔ ✔ ✔
Biotechnology therapeutic products ✔ ✔
Gene therapy medicinal products and applications ✔ ✔
B)Practical part:
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Course contents / Domain 1 Domain 2 Domain 4

K. elements 1.1.1.1 1.1.1.2 1.1.3.1 1.1.3.2 2.2.4.1 2.2.4.2 4.1.2.1 4.3.2.1
Pre-formulation (Physical properties of the drugs). ✔ ✔
Pre-formulation (Solubility and chemical properties of the
✔ ✔
drugs)
Targeted drug delivery (Main mechanisms of targeting) ✔ ✔ ✔
Targeted Drug Delivery Strategies ✔ ✔ ✔

Nano-sized drug delivery systems: Techniques for nanoparticles ✔ ✔ ✔ ✔
preparation (Solid lipid nanocarriers, liposomes)
Nanocarriers‑strategies of the targeting mechanism ✔ ✔ ✔
Conventional nanoparticles preparation techniques ✔ ✔ ✔
Characterization Techniques of nanocarriers (part 1) ✔ ✔ ✔
Characterization Techniques of nanocarriers (part 2) ✔ ✔ ✔
Implants: applications of implantable drug delivery systems. ✔ ✔ ✔
Polymers: applications of polymers ✔ ✔ ✔
Biotechnology therapeutic products: Formulation ✔ ✔ ✔
Considerations of Biopharmaceutical
Stability of Protein Based Pharmaceuticals ✔ ✔
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9. Matrix between course contents and methods of learning and assessment

A) Theoretical part:
Teaching and learning Assessment
methods methods
Collaborative
Course work
Course Content
Advanced
Periodical/
Learning
learning
learning:
Hybrid
lecture
Written
Oral
Self-
Introduction of pre-formulation. √ √ √ √ √
Physical properties of the drugs and their effects on √ √ √ √ √
pre-formulation.
Stability and chemical properties of the drugs and √ √ √ √ √
their effects on pre-formulation.
Targeted drug delivery (introduction, general √ √ √ √ √
concepts).
Mechanisms of targeting and strategies √ √ √ √
Targeted Drug Delivery Strategies √ √ √ √
Nano-sized drug delivery systems (introduction, √ √ √
advantages).
Nano-sized drug delivery systems (types). √ √ √ √
Functionalization of nanocarriers and drug loading √ √ √
in nanocarriers.
√ √
(Self-learning topic: liposomes, solid lipid √
nanoparticles).
Implants: introductions, advantages and √ √ √ √ √
applications.
Polymers (natural polymers) √ √ √ √ √
Polymers (synthetic polymers) √ √ √ √

Biotechnology therapeutic products √ √ √ √
Gene therapy medicinal products and applications √ √ √ √
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B) Practical part:
Teaching Assessment
and learning methods
methods
Course Content
Course work
works and
Periodical/
Learning
Practical
Practical/
tutorials
tutorials
Hybrid
Pre-formulation (Physical properties of the drugs). √ √ √ √
Pre-formulation (Solubility and chemical properties of √ √ √ √
the drugs)
Targeted drug delivery (Main mechanisms of targeting) √ √ √ √
Targeted Drug Delivery Strategies √ √ √ √
Nano-sized drug delivery systems: Techniques for √ √ √
nanoparticles preparation (Solid lipid nanocarriers,
liposomes)
Nanocarriers‑strategies of the targeting mechanism √ √ √
Conventional nanoparticles preparation techniques √ √ √
Characterization Techniques of nanocarriers (part 1) √ √ √
Characterization Techniques of nanocarriers (part 2) √ √ √
Implants: applications of implantable drug delivery √ √ √
systems.
Polymers: applications of polymers √ √ √
Biotechnology therapeutic products: Formulation √ √ √
Considerations of Biopharmaceutical
Stability of Protein Based Pharmaceuticals √ √ √
Course Coordinator Prof. Dr. Marwa Salah El-Din El-Dahhan
Head of Department Prof. Dr. Irhan Ibrahim Abu Hashim
11
Chapter 1
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Preformulation
Physical characteristics
Powder characteristics
 The powder can be characterized by the following parameters: flow behavior, bulk density,
tapped density, true density, etc.
Powder flow properties
 Sufficient flow is required for uniformity of dosage form. So it is necessary to judge the
flow of material in preformulation stage of the dosage form.
 However extreme increase in flow may improve weight uniformity but may reduce content
uniformity through increased segregation.
 The flow properties depend upon following:
1. Force of friction.
2. Cohesion between one particles to another.
 Why inter-particle cohesion is found: it may be due to existence of non-specific Vander

Waal's force or may be due to high moisture content of the sample; it may also be resultant
of surface tension between the sample and media absorbed by it.
 It may also be attributed to the forces experienced due to contact or friction that the powder
sample experiences while in contact with the equipment.
 Angle of repose: it is the simplest of all parameters but plays a predominate role in
describing the inter-particle cohesion. If the cohesive force is dominant in a powder sample,
then its flow will be poor while it’s reversed true when cohesive forces are less.
 θ < 25º implies very good flow behaviour.
 25 º < θ < 50º implies satisfactory flow.
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 θ > 50º implies unsatisfactory flow behaviour.

Factors affecting flow properties:
• Particle size and Particle size distribution
(Fine particles possess poor flow by filling void spaces between larger particles causing
packing & densification of particles).
• Particle shape and Surface roughness
• Density and Porosity
• Hygroscopicity
• Electrostatic charge
Improvement of Flowability
 By addition of glidant e.g., Starch, Talc.
 By particle size enlargement
 By wet granulation
 By densification with the help of slugging (dry granulation)
 By removing static charge
 Using auger feed equipment, mainly to produce a continuous dosing flow.
 By addition of flow activator. E.g., MgO
 By use silicon treated powder for Hygroscopic & moist powder. e.g., silicon coated
talc or Na-bicarbonate
 By altering process condition like vibration assisted hopper or forced feeder
 By use of spray drying: Advantose 100 “spray dried maltose powder” has improved flow
property than Microcrystalline cellulose (MCC) by using this process.
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Compression behavior study

 Measurement of free-flowing powder by compressibility.
 Also known as Carr's index.
CARR’S INDEX (%) = (TAPPED DENSITY – POURED DENSITY) X 100

TAPPED DENSITY
 It is simple, fast & popular method of predicting powder flow characteristics.
Relationship between powder flowability and % compressibility
NO % Compressibility range Flow descriptions
1 5-15 Excellent (free flowing granules)
2 12-16 Good (free flowing powder granules)
3 18-21 Fair to passable (powder granules
4 23- 28 Poor (very fluid powder)
5 28-35 Poor (fluid cohesive powder)
6 35-38 Very poor (fluid cohesive powder)
7 >40 Extremely poor (cohesive powder)
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Depending on the compression characteristics type of material may be:

1. Plasticity
• Plastic materials are capable of permanent deformation, also exhibit a degree of
brittleness (fragmentability)
• But plastic material will get bonding after Viscoelastic deformation.
2. Fragmentability
• If material is fragmentable, neither lubricant mixing time nor dwell time affecting the
tablet strength.
3. Elasticity
E.g., paracetamol, acetyl salicylic acid
• If material is elastic, it rebound when compression force is released.
• Elastic material may lead to capping & lamination.
• They require wet massing to induce plasticity or plastic tableting material.
4. Punch Filming [Sticking]:

• This may lead to chipping of tablet.
Methods of Improvement:
• If plastic material, add fragmentable excipient e.g., Lactose.
• If elastic material  By plastic tableting material, Wet granulation, Pre compression.
• If sticky material  By change in salt form, By using high excipient ratio, By wet
massing, By addition of Mg-stearate.
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Density
The ratio of mass to volume is known as density.
Density = Mass (gms.)/ Volume (ml.)
• Types of density:
(a) True density

(b) Bulk density
(c) Tapped density
(d) Granule density: may affect compressibility, tablet porosity, disintegration,
dissolution. True Density (g/cm3): It’s defined as the density of a powder bed excluding
the volume of its pores either (open or closed).
• True density usually explains about packability and behavior of the powder when
used in binary mixtures at various proportions.
• It’s basically determined by displacement method utilizing either an insoluble solvent

or through gas displacement using helium gas.
• Bulk density: Unlike true density this parameter measures the density of powder bed
taking the volume of closed pores into account.
• Bulk density: It’s also called the apparent bulk density of a powder and is expressed
in terms of g/cm3. It is calculated by the formula:
𝐴𝑝𝑝𝑎𝑟𝑒𝑛𝑡 𝐵𝑢𝑙𝑘 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 = 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑜𝑤𝑑𝑒𝑟/𝐵𝑢𝑙𝑘 𝑣𝑜𝑙𝑢𝑚𝑒

𝑇𝑎𝑝𝑝𝑒𝑑 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 = 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑜𝑤𝑑𝑒𝑟/ 𝑇𝑎𝑝𝑝𝑒𝑑 𝑣𝑜𝑙𝑢𝑚𝑒
Why do we measure 𝐵𝑢𝑙𝑘 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 and 𝑇𝑎𝑝𝑝𝑒𝑑 𝐷𝑒𝑛𝑠𝑖𝑡𝑦?
• To know the compactability of the powder bed when formulating tablet.
• In case of capsule, helps to select the size of capsule for filling the active principle
based on dose.
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Porosity
• Porosity: its synonym is void fraction and its measurement of void spaces or empty
spaces of a powder bed.
• It is calculated as ratio of volume of voids: total volume. It lies between 0 and 1.
• This parameter plays a significant role in deciding the powder behavior, selection of
composition of final formulation, the selection of various unit operations that may be
needed for developing the final product.
• The porosity also decides upon various parameters like selection of granulation method,
hardness of formulate tablets, disintegration of tablets, dissolution rate, thereof.
𝑃𝑜𝑟𝑜𝑠𝑖𝑡𝑦 = 𝑉𝑜𝑖𝑑 𝑣𝑜𝑙𝑢𝑚𝑒 / 𝐵𝑢𝑙𝑘 𝑣𝑜𝑙𝑢𝑚𝑒

= 1 − (𝜌𝑏𝑢𝑙𝑘 / 𝜌𝑡𝑟𝑢𝑒)
Rheology
(A) Definition
It describes flow of liquid and/or deformation of solid under stress.
(B) Types of flow
• Newtonian flow
• Non-Newtonian flow
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Newtonian flow
It is a flow in which a direct proportionality exists between shear stress and shear rate. E.g.,
water, simple organic liquid & dilute suspension, Glycerin.
(C) Determination of viscosity

• Capillary viscometer
• Falling sphere viscometer
• Cup and bob viscometer
• Cone and plate viscometer
• Brook field viscometer
• Ultrasonic Shear Rheometer: For analyzing protein solution rheology.
• Instron Capillary Rheometer: Measures viscosity as a function of rate of shear & temp
at a high rate of shear.
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D) Importance
[1] Fluid
• For mixing
• For particle size reduction of disperse system
• Passing though orifice, pouring, packaging in bottle, passing though hypodermic needle.
• Flow though pipe
• Physical stability of disperse system.
[2] Quasisolids
• Spreading and adherence to skin
• Removal from jar
• Capacity of solids to mix with liquid.
• Release of drug from base
[3] Solids
• Flow of powder from hopper and into a die cavity in tableting or in encapsulation.
• Packagability of powder or granules solids.
[4] Processing
• Production capacity of the equipment
• Processing efficiency
Thixotropy:
• In thixotropy apply shear stress convert gel – sol & remove shear stress convert sol –
gel, means gel to sol to gel.
• Application: for stability of suspension
• e.g., conc. Parental suspension containing 40-70% w/v of procaine penicillin G.
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A. Solubility Analysis
Solubility is the amount of substance that passes into solution to establish

equilibrium at constant temperature and pressure to produce a saturated solution.
Methods of solubility Determination:
(1) Equilibrium solubility method
(2) Turbidometric solubility method
(3) Nephelometric solubility method
(4) Ultrafiltration LC/MS solubility method
(5) Direct solubility method
(B) Ionization constant (pKa):
 Henderson-Hasselbalch equation:
pH = pKa + log [ionized form] / [unionized form] --- for acids.

pH = pKa + log [unionized form] / [ionized form] --- for bases.
• Uses of these equations:
 To determine pKa.
 To predict solubility at any pH provided that CO & pKa are known.
 To facilitate the selection of suitable salt forming compounds.
 To predict the solubility & pH properties of the salts.
Methods to determine pKa:

• Potentiometric method.
• Conductivity method.
• Dissolution rate method.
• Liquid-Liquid partition method.
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• Spectrophotometric method.
Partition Coefficient:
• Partition Coefficient (oil/ water) is a measure of a drug’s lipophilicity and an indication
of its ability to cross cell membranes. It is defined as the ratio of unionized drug
distributed between the organic and aqueous phases at equilibrium.
• In formulation development, the n-octanol/water partition coefficient is commonly

used.
• For unionizable drugs P = (Concentration of drug in octanol)

(Concentration of drug in water)
• For ionizable drugs P = (Concentration of drug in octanol)

(1-α) X (Conc. of drug in water)
Where α = degree of ionization.
P > 1  Lipophilic drug.
P < 1  Hydrophilic drug.
Methods to determine P:
• Shake Flask Method.
• Chromatographic Method (TLC, HPLC).
• Counter Current & Filter Probe method.
Factors affecting solubility:

Thermal effect:
Effect of temperature on the solubility of drug can be determined by measuring heat of
solution. (∆Hs).
ln S = -∆Hs/R*T + C
where, S = Molar solubility at temperature T (ºK).
R = Gas constant.
22
Heat of solution represents the heat released or absorbed when a mole of solute is
dissolved in a large quantity of solvent.
Typical temperature range should include 5ºC, 25ºC, 37ºC & 50ºC.
Importance: Determination of temperature effect on solubility helps in predicting storage
condition & dosage form designing.
Common ion effect:
 To identify a common ion interaction, the Intrinsic Dissolution Rate of HCl salt should
be compared between
a) Water & water containing 1.2% W/V NaCl.
b) 0.05 M HCl & 0.9% NaCl in 0.05 M HCl.
 Both saline media contains 0.2 M Cl‫ ־‬which is typically encountered in fluids in vivo.
Dissolution:
 The absorption of solid drugs administered orally can be understood by following
flowchart.
Dissolution rate can affect:

• Onset of action
• Intensity of action.
• Duration of response.
• Control the overall Bioavailability of drug form.
23
Dissolution is to be considered of 2 types:

• Intrinsic dissolution
Noyes-Whitney equation:
To predict if absorption would be dissolution rate limited or not.
dm/dt = AD(Cs-C) / h
Where, dm/dt = rate of mass transfer / rate of dissolution
D = diffusion coefficient
A= surface area of solute particles
Cs = concentration of solute particles at donor compartment
C= concentration at acceptor site/compartment
h = height of the boundary layer
When dissolution is controlled solely by diffusion the rate of diffusion is directly
proportional to the saturated concentration of the drug in solution under these conditions
the rate constant K1 is defined by:
K1 = 0.62 D2/3 v 1/6 w1/2
Where, v is the kinemative viscosity.
w is the angular velocity of a rotating disc of drug.
Method to determine intrinsic dissolution:

Rotating disk method or Wood’s apparatus: For determination of dissolution from constant
surface area.
• Particulate dissolution:
Determine the dissolution of solids at different surface area.

It is used to study the influence on dissolution of particle size, surface area & mixing with
excipients.
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Chemical characteristics
• Oxidation
It is a very common pathway for drug degradation in both liquid & solid formulation.
Analysis of oxidation:
Drug’s sensitivity to oxidation can be examined by exposing it to atmosphere of high
oxygen tension.
Usually, a 40% oxygen atmosphere allows for rapid evaluation.
A shallow layer of drug exposed to a sufficient headspace volume ensures that the
system is not oxygen limited.
Samples are kept in desiccators equipped with three-way stop cocks, which are
alternatively evacuated and flooded with desired atmosphere.
The process is repeated 3 or 4 times to ensure 100% desired atmosphere.
Results may be useful in predicting if an antioxidant is required in the formulation or if
the final product should be packaged under inert atmospheric conditions.
• Photolysis
Mechanism of decomposition:
 Electronic configuration of drug overlaps with spectrum of sunlight or any artificial
light, & thereby energy is absorbed by electron & it goes to the excited state.
 They are unstable & release the acquired energy & come to the ground state &
decompose the drug.
Photodecomposition pathways:
 N-Dealkylation:
E.g., Diphenhydramine, Chloroquine, Methotrexate.
25
 Dehalogenation:
E.g., Chlorpropamide, Furosemide.

 Dehydrogenation of Ca++ channel blocker.
E.g., Solution of Nifedipine → Nitrosophenylpyridine (with loss of water).
Rapidly yellow color
Brown.
 Decarboxylation in anti-inflammatory agents.
E.g., Naproxen, Flurbiprofen, Benzoxaprofen.

 Oxidation.
E.g., Chlorpromazine & other phenothiazines give N- & S- oxides in the

presence of sunlight.
 Isomerization & cyclization.
E.g., Noradrenaline, Doxepine.

 Rearrangement.
E.g., Metronidazole → Oxidiazine → Yellow color.
26
Chapter 2
27
Targeted drug delivery
 Targeted drug delivery systems (TDDS) involve the administration of the DDS to the
patient, its delivery at the target (pathological) site, release of the active ingredients
in/around the target and avoiding nonspecific toxicity in normal cells.
Main mechanisms of targeting
A- Passive (Physiology-Based) Targeting

 Passive targeting is present naturally in the human body. Hormones, neurotransmitters,
growth factors can target the receptors at their sites of action, e.g., insulin and insulin
receptors.
 Passive targeting is achieved by incorporating the therapeutic agent into a

macromolecule or nanoparticle that passively reaches the target organ. In passive
targeting, the drug's success is directly related to circulation time. This is achieved by
cloaking the nanoparticle with some sort of coating.
B- Active Targeting
 It involves modifications and functionalization on the drugs or drug carriers afford them
affinity towards specific receptors/markers on cells, tissues, or organs.
 Factors such as the disease, the intended target organ, and a larger presence of targetable
components on the target organ/cell (e.g., transferrin receptors in tumor) than in normal
cells are taken into consideration while deciding on the targeting moiety to be attached to
the therapeutic substances.
28
Methods of active targeting
I- Targeting Mediated by External Stimuli

 External stimulus, such as magnetic field (magnetic nanoparticles) and ultrasound,
and hyperthermia acting on nanocarriers, are employed to target and release drugs from
the nanocarriers at the intended site of action.
 The approach can also combine different external stimuli, for example, ultrasound
and magnetic field, for enhanced targeting and efficiency. E.g. the use of magnetic
nanoparticles (MNP) as imaging agents for magnetic resonance imaging, magnetic drug
targeting and hyperthermia treatment can be used.
 The magnetic nanoparticles include superparamagnetic iron oxide nanoparticles

that are commonly used because of
-nontoxic nature,
-ability to be functionalized with different targeting coatings
-and can encapsulate drugs in reasonable quantity.
 Ultrasound has been used for contrast imaging and drug delivery because
ultrasound can cause reversible disruptions in the intravascular endothelial layers creating
pores for the drug to enter the extracellular space of the target tissue. This occurrence was
also observed with blood–brain barrier/blood–tumor
29
External stimulus of focused ultrasound leads to ( a ) reversible disruptions and gaps

in the epithelial cell layer allowing drugs/drug nanocarriers to escape the blood vessels
into the target tissues, ( b ) disruptions to the nanocarriers to release the drugs around
the target tissue barrier.
 In temperature-sensitive nanocarriers, the generation of hyperthermia can provide

cytotoxic for nearby tissues and in case of tumor treatment this is highly beneficial. The
hyperthermia will kill tumor periphery cells and open the way for simultaneously
administered drugs to enter the core of tumor tissue for enhanced killing.
II- Antibody-Directed Enzyme Prodrug Therapy (ADEPT)
 This approach is a two-step approach:
(1) An activating enzyme is specifically delivered to intended site of action with a

targeting antibody (e.g., tumor-specific antibody)
(2) A subsequent administration of substrate prodrug.
30
 The advantage with such a system is a single enzyme at the target site can activate
multiple prodrugs and increase the load at the target site.
Targeted Drug Delivery Strategies

A- Disease-Based Strategies
1- Cancer Specific Strategies

2- Targeted Drug Delivery towards Infections
B- Specific Location-Based Strategies
1. Blood–Brain Barrier (BBB) Targeted Delivery

2. Targeting Drug Delivery to the Skin with Highlight on the Follicular Pathway
3. Pulmonary Targeted Drug Delivery
4. Retina drug targeting
5. Colon Targeted Drug Delivery
6. Intracellular Targeting
*****************************************
Retina drug targeting
 Topical administration involves the use of solutions and ointments as drug delivery
systems, and they are excellent choices for anterior segment of the eye and are patient
friendly and cost appropriate too.
 But, these systems usually do not deliver drugs at effective levels at the retina which
lies in the posterior parts of the eye due to drug loss due to washing off by tears,
metabolism by the anterior segment enzymes and impermeability of the corneal
epithelium. Hence, as a route for targeted delivery to the retina, topical administration
does not suit well.
31
 The intravitreal injection is uncomfortable for the patient and frequent dosing is
associated with high probabilities of injection associated infections and retinal
detachment.
Overcome: using PLGA nanocarriers, implants and lipidic prodrugs.
Examples
1- The use of intravitreal implants can give a sustained delivery for a longer period as
compared to the injections; up to 6 months. Such a delivery system is especially
beneficial to patients with chronic eye disorders.
2- Scleral implants made from polymers such as poly (DL-lactide-co-glycolide) (PLGA)

and ploy (DL-lactide) (PLA) were used to deliver gancyclovir with a sustained release
of therapeutically effective doses obtained.
32
Colon Targeted Drug Delivery

 Several diseases like inflammatory bowel diseases (IBD), ulcerative colitis, colon
cancer, irritable bowel syndrome (IBS), amoebiasis, etc. and desired transport of proteins
and peptide drugs require the use of colon targeted drug delivery systems (CDDS).
 The general routes of reaching the colon are via the oral delivery or the rectal delivery.
Using the rectal mode of administration is usually uncomfortable for the patient and can
often result in irregular dose distribution.
 Conversely, using regular oral modes of delivery can degrade the drugs by acid actions
in the stomach and alkaline and enzyme activity in the small intestine. Hence, for
appropriate colon-specific delivery targeted systems should be utilized.
 Types of CDDs are pH-dependent, time-dependent, and microflor enzyme dependent
systems.
Disadvantages
 -It is possible that the pH-dependent system may survive the passage through the stomach
but not the small intestine. The time-dependent system usually depends on the natural
time for food and drug to passage through the gastrointestinal tract (GIT) which can be
irregular in the diseased states.
Overcome: Improved technologies such as di-dependent systems utilize control by

two factors to release the drug.
For example, CDDS that depended on pH and microbes to deliver the drugs consisted
of a traditional tablet core containing lactulose with additional layers of Eudragit E
(acid soluble) and Eudragit L (enteric coat) on top of it, in that order, was developed
to protect the active drug from the acid effects of the stomach (enteric coating), the
alkaline pH of small intestine (acid soluble coating) and deliver to the colon wherein
the lactulose would be degraded by the colon bacteria. The enzymatic degradation of
33
the lactulose would produce organic acids lowering the pH locally and dissolve the
acid soluble coat releasing the drugs.
 An alternative technique that can be used is to make prodrugs which provide protection
in the upper GIT but undergoes enzymatic degradation in the colon to release the active
drug. For example, glycosidic prodrug of dexamethasone and prednisolone. The
prodrugs were not absorbed in the small intestine as they were hydrophilic thus reaching
the colon intact. Once in the colon, the bacterial glycosidases cleaved the prodrugs to
release the active drugs.
 The intrinsic ability of nanoparticles to accumulate at inflammation sites is also studied

for targeted delivery to the colon esp. in case of IBD. This results in long term deposition
of the nanoparticles and drugs within at the site of inflammation.
34
Intracellular Targeting
 Once the therapeutics can reach the intended organ/tissue of action, they need to act
either extracellularly or intracellularly.
 When the action is supposed to occur in extracellular regions, the task of arriving at the
specific organ/tissue is enough.
 Yet when the mechanism of action of the therapeutic substance is on specific proteins,
peptides, enzymes, nucleic acids (DNA/RNA) which are present within the cell, the
TDDS needs to go a step or even two, in case of nuclear targeting, further, to ensure
that the specific drug/gene enter the cell and are in active form once they reach their
intracellular targets.
Methods of intracellular targeting:
I- Endocytosis
 Endocytosis is a cellular process in which substances are brought into the cell. The
material to be internalized is surrounded by an area of cell membrane, which then buds
off inside the cell to form a vesicle containing the ingested material. Endocytosis
includes pinocytosis (cell drinking) and phagocytosis (cell eating). It is a form of active
transport.
 It is the process of absorbing molecules by the cells, three ways of which are:
phagocytosis, pinocytosis, and receptor- mediated endocytosis (RME).
 The early endosomes are characterized by mildly acidic pH. The early endosomes
mature into the late endosomes that also have mildly acidic pH (5.5) and result in
formation of lysosomes after final sorting of the internalized material. Lysosomes are
acidic and contain hydrolytic enzymes that degrade the material within.
 An acidic pH-sensitive system will, on entry into the endosomes, disintegrate to release
35
the drug payload which can diffuse into the cytoplasm.
 If the drug is internalized by endocytosis, it is possible to initiate its release into the
cytoplasm via endosome-disruption.
36
II- The cell penetrating peptides (CPPs)
 Cell-penetrating peptides (CPPs) are short peptides that facilitate cellular intake and
uptake of molecules ranging from nanosize particles to small chemical compounds to
large fragments of DNA.
 They enter the cells and directly release the payload. Multiple disease and disorders
find their pathology to involve the role of mitochondria. Consequently, drugs and
nucleic acids with actions on mitochondria are useful to target the mitochondria after
entering the cytoplasm.
 Targeting peptides can be used for cell penetration and mitochondrial targeting to
benefit patients of cancer.
 Gene therapy usually requires that the nucleic acids be delivered into the nucleus where
the nuclear membrane forms an additional barrier. The usual approaches to gene
therapy use viral-mediated as well as nonviral (e.g., liposomes) gene delivery.
37
Chapter 3
38
Nano-sized drug delivery systems
 Drug delivery is the process of transportation of a therapeutic agent into the body with
appropriate pharmacokinetics, thereby creating the desired action.
 Nanocarriers are simply colloidal nanoparticles widely used for the transportation of a
therapeutic agent or any other substances to a target site. The size of the nanocarriers
lies between 1 and less than1000 nanometer (nm) in diameter
39
1- Solid lipid nanocarriers (SLNs)
Solid lipid nanoparticles (SLNs) are colloidal carriers of nanoscopic size (50– 1000
nm), made up of solid lipids (high melting fat matrix) that are emerged in 1991.
Compositional Profile of SLNs
 Lipid and surfactant/stabilizer are the key components used to fabricate SLNs along
with co-surfactant, preservatives, cryoprotectant, and charge modifiers.
 By reducing the interfacial tension between the aqueous environment and the
hydrophobic surface of the lipid core, surfactants help in stabilizing the SLN
structure.
40
Fabrication Techniques of SLNs
 Techniques such as ultra-sonication or high-speed homogenization, cold

homogenization, hot homogenization, solvent emulsion/evaporation methods,
double emulsion methods, and spray drying methods have been widely employed
for the fabrication of SLNs.
 The solid lipid nanocarriers are prepared by the dispersion of melted solid lipids in
water and stabilized by adding emulsifiers through micro-emulsification or through
high pressure homogenization.
 The conventional solid lipid nanocarrier can be easily eliminated by Reticule

Endothelial System.
 Recently, the solid lipid nanocarrier can be used to incorporate ionic and
hydrophilic anticancer drugs along with the lipophilic drug.
 Certain new generation nanocarriers such as nanostructured lipid carrier (the

mixture of liquid lipid and solid lipid) and lipid drug conjugates (water insoluble
carrier molecule) are found to overcome the drawbacks of conventional solid lipid
nanocarrier.
41
 This nanocarrier can be used for drug delivery through topical application,
parenteral and oral administration.
2. Liposomes
 They are lipid bilayers enclosing an aqueous core which forms a spherical vesicle
that can be used to deliver both lipophilic and hydrophilic drugs at target site.
 The bilayer can differentiate it into unilamellar vesicle (one bilayer) or
multilamellar vesicle (more than one bilayer).
 This vesicle serves as an agent to transport biologically active molecules at the
specific site.
 However, these molecules have short half-life period in the systemic circulation.
Overcome
Therefore, liposomes can be coated with polymeric molecules like polyethylene glycol
to form PEGylated liposomes to provide high stability and long half-life period in the
blood by escaping from the Reticule Endothelial System elimination producing a
sustained drug release.
42
Methods of liposome preparation

General methods of preparation
All the methods of preparing the liposomes involve four basic stages:
1. Drying down lipids from organic solvent.
2. Dispersing the lipid in aqueous media.
3. Purifying the resultant liposome.
4. Analyzing the final product.
43
Method of liposome preparation and drug loading

The following methods are used for the preparation of liposome:
1. Passive loading techniques
2. Active loading technique.
Passive loading techniques include three different methods:

1. Mechanical dispersion method.
2. Solvent dispersion method.
3. Detergent removal method (removal of non-encapsulated material).
Mechanical dispersion method
The following are types of mechanical dispersion methods:
1.1. Sonication.
1.2. French pressure cell: extrusion.
1.3. Freeze-thawed liposomes.
1.4. Lipid film hydration by hand shaking, non-hand. shaking or freeze drying.
1.5. Micro-emulsification.
1.6. Membrane extrusion.
44
Nanocarriers‑strategies of the targeting mechanism
 The major strategies for targeting nanocarriers to the specific site include:
• Administration of nanocarriers at the target site directly
• Directing magnetic nanocarriers using magnetic fields
• Active targeting
• Passive targeting
1- Active targeting
 The active targeting strategy is based on that small ligand molecules on the surface
of the nanocarriers actively bind to the specific receptor, to be retained at the target
site and actively uptaken by the diseased cells.
 This approach is the widely accepted one and has high selectivity in binding the
target site with high affinity.
 The binding ligand should have specificity in determining the protein receptors
overexpressed in the diseased cells which are absent in the healthy one.
 For example, cancer or tumor cells have overexpressed proteins on their surface.
This active targeting enables increased intracellular uptake of the drug by the
diseased cells.
 The targeting ligands include the small molecules, lectins, antibodies, lipoproteins,
peptides, hormones, glycoproteins (transferrin), polysaccharides, low molecular
weight vitamins (folic acid), nucleic acids and growth factors.
 The nanocarriers can also be modified to target multiple moieties as they have a
high surface-to-volume ratio.
45
 The active targeting is advantageous over passive targeting as it can reduce multi-
drug resistance.
 This is due to the specific receptors that are expressed only in the cancer cells. For
instance, Transferrin receptor in breast cancer cells, and folate receptors in ovarian
or lung cancer cells.
 The use of folate ligands has the advantage of its small size with molecular weight
~ 441 kDa than the antibodies with molecular weight ~ 160,000 kDa. The smaller
size molecule penetrates more easily to the distant target site than the larger one.
 Active targeting of the endothelial cell is another strategy for bypassing endothelial
barrier and target tumor cells.
2- Passive targeting
 Enhanced permeability and retention effect is the basic route for passive targeting.
 The deadly disease like cancer leads to leaky vasculature with endothelial cell
dimension many folds (50–70 fold) more than that of the healthy blood vessels.
Therefore, nanocarriers with molecular weight more than 40 kDa can extravasate
through the leaky vasculature of inflamed area or tumor tissue.
 Passive targeting of this leaky vasculature can enable the nanocarriers to enter
through the interstitial space in the endothelial barrier enhancing the drug
conjugated nanocarrier to accumulate at the disease site. This effect is known as the
enhanced permeability and retention effect.
 This enhanced permeability and retention effect prevents the undesired side effects
by the target-specific accumulation of drug at the diseased site.
 The targeting of nanocarrier with low molecular weight drug has the drawback of
diffusing away from the target site and re-entering the blood circulation.
46
 The accumulation of nanocarrier at the target site depends on its charge due to the
functional group and its size. The nanocarriers with hydrophilic surface and size
less than 200 nm are found to have enhanced permeability and retention effect as
their blood circulation time is higher.
 Though the enhanced permeability and retention effect has a greater impact on the
passive targeting of tumor cells, this enhanced permeability and retention effect is
not found in every tumor cells. This size dependent enhanced permeability and
retention effect is heterogeneous for different tumor and for different patients.
 Enhanced permeability and retention effect is also affected due to the high fluid
pressure and variable endothelial gaps.
 Nanocarrier based on passive targeting reached clinical studies and are promising
to be scaled up. For example, reaching the clinical use is DOXIL™ which is
doxorubicin in PEGylated liposome.
47
48
 Mechanism of nanocarriers targeting. In active targeting, the drug-loaded

nanocarriers with receptor specific ligands circulates in the blood stream and release
the drug at the target tumor site. While, in passive targeting, the enhanced
permeability and retention effect enables the drug conjugated nanocarriers to
penetrate deep into the tumor site).
Conventional nanoparticles preparation techniques
1-Nanoprecipitation
 Nanoprecipitation is also called solvent displacement or interfacial deposition method.
 In the nanoprecipitation method, the nanoparticles are obtained in the colloidal

dispersion when the oil (organic) phase is slowly added to aqueous phase under a
moderate stirring. Formation of the nanoparticles is instantaneous and needs only one
step, so it has the advantage of rapid and easy operation.
 The key parameters in the fabrication procedure that have great influence on the
nanoprecipitation method are:
 organic phase injection rate,
 aqueous phase agitation rate
 and the oil phase/aqueous phase ratio.
 Particle sizes of very narrow distribution can be obtained because of the absence of
shearing stress.
 This method is used mostly for hydrophobic drug entrapment, but it is also employed
sometimes to incorporate hydrophilic drugs.
49
 Technique:
1- Polymer and drug are dissolved in a water miscible organic solvent, for example,
acetone or methanol.
2- the solution is then added into an aqueous solution which contains a stabilizer in a
drop-wise manner.
3- Through rapid solvent diffusion, the NPs are formed immediately. After that, the
solvents are removed under reduced pressure.
 Advantages:
1- Particle size formed by this method is usually around 200 nm, typically smaller than
those produced by other processes.
2- The method can be applied to a wide range of polymers, peptides and amphiphilic
cyclodextrins,
3- rapid and easy
 Disadvantages
Scale up would be inefficient due to the nature of drop-wise addition.
Preparation of nanoparticles by nanoprecipitation
50
2- Emulsion evaporation method
 The basis technique:
1- The method is based on the emulsification of polymer organic solution into a water
phase, followed by organic solvent evaporation.
2- The polymer is first dissolved in a suitable solvent (e.g., ethyl acetate, chloroform,
or methylene chloride).
3- The organic phase is poured into the continuous phase (aqueous phase) in which a
surfactant is dissolved to impart stability to the emulsion.
4- Emulsification is carried out under high-shear force to reduce the size of the emulsion
droplet. This process will largely determine the final particle size.
5- After the formation of emulsification, the system evaporates the organic solvent
under vacuum, which leads to polymer precipitation and nanoparticles formation.
Preparation of nanoparticles by emulsion evaporation method
51
 Disadvantages:
1- Nevertheless, this is a slow process compared to nanoprecipitation which happens in

milliseconds. For instance, it requires 80 min to evaporate 10 mL of ethyl acetate from
a 50 mL aqueous emulsion.
2- The coalescence of emulsion droplets during evaporation determines the final

particle size which is largely dependent on the evaporation condition.
Overcome:
i- Adjusting solvent evaporation conditions such as temperature and pressure would

improve the quality.
ii-The use of a surfactant such as sodium dodecyl sulphate (SDS) or poly(vinyl alcohol)
(PVA) would also minimize the coalescence effect and produce smaller nanoparticles.
3- The loading level for hydrophilic drugs, such as proteins and peptides, is generally
poor due to diffusion of the hydrophilic drug into the aqueous phase before the polymer
can solidify to entrap the drug.
To overcome this problem, water-in-oil-in-water (W/O/W) double emulsion can be

used to reduce the loss and to preserve the bioactivity of delicate drugs such as proteins
in the aqueous phase.
 Double emulsion technique
 The primary emulsion is formed by ultrasound treatment of a mixture of aqueous phase

containing therapeutics and organic phase containing the polymer and an organic
surfactant serving as the stabilizer for water-in-oil (W/O) emulsion.
 The second emulsion is formed by sonicating a mixture of the organic phase
containing dispersed W/O emulsions and aqueous phase containing a hydrophilic
stabilizer.
52
 Sonication duration for the second step is more critical in determining the final particle
size as compared to that of the first step and surfactant concentration.
 Longer sonication time significantly reduces the size of the particles and produces
smaller polydispersity, but this must be balanced against the potential risk of damaging
the drug.
3. Emulsion diffusion method

 There are single emulsion and double emulsion systems in this fabrication method.
Single emulsion encapsulation method is conducted for the formulation of oil soluble
(hydrophobic) substances, while double emulsion is adopted by entrapment of
hydrophilic chemicals.
 Steps:
1- In this method, the polymer is dissolved in a partially water-miscible solvent (such as

benzyl alcohol and propylene carbonate) which is pre-saturated with water.
2- A typical emulsification method is then used to produce oil-in-water (O/W) emulsion

droplets from the water-polymer saturated solvent.
3- The dispersed droplets are then diluted by a large amount of water containing a
stabilizer.
4- The diffusion of organic solvent out from the droplets leads to the condensation of the
materials within the droplet and formation of nanoparticles.
53
Preparation of nanoparticles by emulsion diffusion method
 Advantages:
1- The solvent extraction process takes places within a few milliseconds, causing a drop in
particle size.
2- In general, the diameter of particles prepared by this method is around 150 nm due to the
fast solvent extraction and the polydispersity is significantly low.
 The factors affecting nanoparticles formation
1- One of the key requirements of the emulsion diffusion method is the selection of an
organic phase (oil phase) containing polymer solution which must be partially miscible
in aqueous phase.
2- The most important fabrication step is solvent diffusion, in which the organic phase
diffuses from the oil phase to outer water phase and the formed particles become
hardened.
3- The selection of the surfactants in the outer water phase is also crucial to the successful
fabrication.
54
 Different kinds of surfactants, such as non-ionic surfactant polyvinyl alcohol (PVA),

anionic surfactant sodium dodecyl sulphate (SDS) and cationic surfactant didodecyl
dimethyl ammonium bromide (DMAB), are commonly applied based on emulsion
systems.
 Different surfactants can induce particles in different sizes. For example, when DMAB
was used as surfactant for the fabrication of PLGA NPs, smaller particles were
fabricated than the ones prepared using PVA as the surfactant.
 Another popular stabilizer for the fabrication of PLGA NPs is amphiphilic D-_-
tocopheryl polyethylene glycol 100 succinate Vitamin E (TPGS) as TPGS has very
high emulsion efficiency. The amount of TPGS used as surfactant usually can be as
low as 0.015% (w/v).
 The amount of surfactant used influences the properties of the NPs.
 Low concentration of surfactants usually leads to a high polydispersity and particle

aggregation.
 Excessive surfactants are used, the drug loading will decrease due to a strong
interaction between the drugs and surfactants.
 Therefore, the suitable concentration of surfactant is the key to successful

fabrication.
 Another method to form the mono-dispersed emulsion is using the probe sonicator to
impose high energy in the formed emulsion. The selection of specific sonicator mode,
time and power is essential to the formation of emulsions.
55
4. Salting out Method

 Technique:
 Firstly, the PLGA is dissolved into the organic solutions (oil phase) which are usually
water miscible. Typical solvents are tetrahydrofuran (THF) and acetone.
 The aqueous phase consists of the surfactant and saturated solution of electrolyte.
 The electrolytes should not be soluble in the organic solvent. Typically, the most used
salts are magnesium chloride hexahydrate with a concentration of 60% (w/w) or
magnesium acetate tetrahydrate which is normally used with a ratio of 1:3 (polymer to
salt).
 The oil phase is emulsified in an aqueous phase, under a strong shearing force by a
mechanical stirrer.
 The obvious difference between the emulsion diffusion method and salting out method
is that there is no solvent diffusion step for the latter one due to the existence of salts.
 To decrease the ionic strength in the electrolyte, the distilled water is added into the
formed O/W emulsion under a magnetic stirrer. At the same time, the hydrophilic
organic solvents migrate from the oil phase to aqueous phase, which results in the
formation of the NPs.
 Finally, the salting out agent is eliminated by centrifugation and the samples are
purified.
56
Preparation of nanoparticles (NPs) by salting out method.
57
Characterization Techniques of nanocarriers

 Various parameters are required to be assessed to understand the fate of nanocarriers.
 These particle size distribution, zeta potential, nature and degree of crystallinity, surface
morphology, intrastructure, solid state characteristics, in vitro release, and storage
stability.
1- Particle Size and Zeta Potential

 Particle size, particle size distribution indicated by polydispersity index (PDI) and zeta
potential are the essential characteristics of nanoparticles that can be evaluated by
Dynamic light scattering (DLS) as one of the most important techniques.
 The speed of analysis, easy sample preparation, and sensitivity to submicrometer

particles are the advantages of this method.
 The size of nanoparticles is an important factor for their physical stability because the
high surface area makes particles tend to aggregate to decrease the high surface energy.
Zeta potential measurements can provide information about the colloidal stability of the
particles as well as shelf life of colloidal dispersions.
 The zeta potential of a particle is the overall charge that a particle acquires in a particular
medium.
 Measurements of zeta potential are commonly used to predict the stability of colloidal
systems.
 If all the particles in dispersion have a large negative or positive zeta potential then
they will tend to repel each other and there will be no tendency to aggregate (flocculate).
58
 However, if the particles have low zeta potential values, then there will be no force to
prevent the particles flocculating
 High values of zeta potential (e.g., greater than ±30 mV) can stabilize the colloidal
dispersion by electrostatic repulsion under given conditions.
 Electrostatic repulsion causes the particles to repel each other, thus avoiding
aggregation.
59
 However, particles with zeta potential near zero under storage conditions may also be
stabilized upon storage. Such stabilization can be achieved by coating the particle with
a hydrophilic polymer (e.g., PEG) to create a physical barrier against aggregation. This
stabilization is known as steric stabilization.
Influence of zeta potential on particle-particle interaction.
2- Entrapment efficiency (EE%):

 Nano-sized preparations are a mixture of encapsulated and un-encapsulated drug
fractions. The first step for the determination of the encapsulation efficiency is the
separation between the encapsulated drug (within the carrier) and the free drug.
60
 Separation techniques have been reported:
 The mini-column centrifugation: it is a method based on the difference of size

between the drug loaded liposomes and the free drug.
 Cooling Ultracentrifugation (50000 rpm, 4ºC, 1h).
 Dialysis against a buffer solution for 2 h
 The entrapment efficiency can be determined by two main methods:
 Direct method by analysis of the encapsulated fraction
EE%  Drug weight in the nanoparticles x100%
Weight of drug and polymer added
 Indirect method by analyzing the free drug fraction
3- Surface Morphology and internal structure

 Electron microscopy techniques such as scanning electron microscopy (SEM) gives 3D
images of the particles to investigate the surface morphology,
 Transmission electron microscopy (TEM) gives information about the size and shape
of nanoparticles as well as internal structure.
 SEM examination is applied using dried samples while TEM can be performed using
nanoparticles dispersions.
 A proper dilution can be done to provide imaging of well-separated particles in case of

TEM examination
61
B C
Example of SEM microphotographs of pure drug irregular particles (A) and rod-
shaped uncoated (B) and coated (C) nanoparticles.
A B
Example of TEM microphotographs of rod-shaped uncoated (A) and coated

nanoparticles (B).
62
Example of SEM microphotographs of pure drug irregular particles (A) and rod-
shaped uncoated (B) and coated (C) nanoparticles.
Example of TEM microphotographs of spherical nanoparticles: uncoated (A)

and coated (B).
63
4- Degree of Crystallinity or amorphous structure (solid-state characterization)

 Degree of crystallinity of dried nanoparticles can be determined with the aid of
differential scanning calorimetry (DSC) which It is a thermo-analytical technique based
on heating the solid sample at a certain rate (degree/min) and record the sharp
endothermic or exothermic peaks that indicate the crystallinity. Its disappearance in the
dried nanoparticles indicates the drug encapsulation within nanoparticles.
 The broad peak indicates either the amorphous nature, water loss, or thermal
degradation
 Powder X-ray diffractometry (PXRD) is another non-destructive method and widely

applied for the description of crystalline materials and analyze the crystal structure of
dried nanoparticles. Presence of several diffraction peaks indicates the crystalline
structure. Their absence proves the amorphous structure of the polymer or the drug
encapsulation within the nanoparticles.
Example of DSC (left) and XRD (right) curves of crystalline drug (1), amorphous
polymers (II, III), physical mixture (IV) and dried nanoparticles (V,VI).
64
5- In vitro release study

 It is performed using the dialysis diffusion technique.
 Some milliliters aliquots of nanoparticles dispersion or a certain weight of dried

nanoparticles is placed in the dialysis bag that is tied and dropped in the donor
compartment that is separated from the receptor compartment containing the dissolution
medium by dialysis (cellophane) membrane
 The entire system is kept at 37 °C under a continuous stirring and the receptor medium
is closed to avoid the evaporation of the dissolution medium.
 Samples of the dialysate are taken at various time intervals and assayed for the drug by
HPLC, spectrophotometer or any other convenient method.
 The sample volume is replaced with fresh dissolution medium so as the volume of the
receptor compartment remains constant.
% drug released = amount released/ total drug in the studied sample
Dialysis cell for in vitro release study
65
50
40
% drug
released
30
20
10
0
0 2 4 6 8 10
Time (h)
Example of in vitro release curve of pure slightly soluble drug (bottom) coated
nanoparticles with more controlled release (middle) and uncoated nanoparticles
(upper)
 The drug is either embedded in the matrix or on the surface, and such a system can show
versatile release or dual release (immediate release with sustained release). Drug
adhered on the surface of nanoparticles will disperse and will show an immediate release
effect, thereafter the matrix can erode or degrade and release the drug in a controlled
manner.
 The immediate release provides the initial required therapeutic levels and the gradual
release maintain these levels. Also this dual release can be observed with homogeneous
matrix nanoparticles due to drug diffusion, matrix erosion or degradation.
Drug-enriched shell model Drug-enriched core model Homogeneous matrix model
66
6- Storage stability
 The stability of the lyophilized selected nanoparticles can be evaluated during the
storage period (3-6 months) at refrigerator (2-8°C) and room (25±1°C) temperatures.
 Nanoparticles were examined regarding particle size, EE% and zeta potential monthly
and compared with the initially determined values at the beginning of the study.
 Insignificant changes in these parameters indicate the storage stability.
 Nanoparticles dispersions are preferred to be dried by spray drying or freeze drying

(lyophilization) to avoid particle aggregation, polymer degradation and improve their
storge stability.
 Cryoprotectants such as lactose and trehalose can be used to avoid disruption and size
enlargement of the nanoparticles during lyophilization.
 Use of solvents with low evaporation temperatures as ethanol or its mixture with water
is recommended during spray drying.
67
Chapter 4
68
Implants
They are subcutaneously introduced products designed to transmit drugs and
fluids into the blood stream without the repeated insertion of needles. Implants are small
pumps inserted under the skin through small surgical operation under local anesthesia.
Applications (examples of implantable drug delivery systems)

I- Implants for insulin delivery (artificial pancreas)
II- Implants for contraception.
III- Implants for chemotherapeutic agents
II. Implants for contraception

Types:
A- Biodegradable
B- Nonbiodegradable
A- Biodegradable implants for contraception
Advantages:
1- They can provide a programmed rate of release of steroids so they eliminate
menstrual abnormalities associated with constant levels of steroids.
2- They can be used for three months or longer.
The primary mechanisms of steroids release are erosion, diffusion, or cleavage of

covalent bonds of the biodegradable polymer. A combination of these processes can occur.
69
The commonly used biodegradable polymers are poly(lactic acid), poly(glycolic

acid), and poly(caprolactone). Accumulation of DL-poly(lactic acid) can occur with
repeated injection. DL-poly(lactide-co-glycolide) can be used as it degrades at a faster rate.
Poly (caprolactone) can release the steroids up to one year suppressing ovulation
without any serious adverse effects.
Contraception occurs at high levels of steroids through inhibition of ovulation. At

low levels of steroids, steroidal hormones can cause alteration in cervical mucus, sperm
migration, ovum transport, and implantation.
B-Nonbiodegradable implants for contraception
The non-biodegradable polymer is shaped into capsules or rods which are implanted
subdermally.
Advantages:
1- The high efficacy.
2-The duration of action is longer than biodegradable implants.
3- The effects can be terminated by removing the implant.
Disadvantages:
1- They may result in menstrual abnormalities and systemic side effects.
2-They need medical personnel to implant and remove them.
3- The possibility of the implants migration and toxic effects.
Example: Norplant
They are Medical-grade silastic capsules 34 mm long

containing levonorgesterel. Six capsules are inserted subdermally into the upper arm
within one week of the onset of menses. It is designed to be used for 5 years. It operates by
interfering with ovulation.
70
III. Implants for chemotherapy
Programmed drug administration devices (DAD) have been used for terminal cancer
pain management and cancer chemotherapy. The life of the device depends on the capacity
of the power source and the drug delivery rate.
The expected duration of these devices is from 3 to 5 years depending on the

application and amount of drug delivered.
In cancer pain management using DAD with morphine sulfate, pain relief was
excellent without side effects found with oral medication such as respiratory depression,
confusion, and constipation.
For cancer therapy, DAD with programmed delivery of floxuridine was superior to
the constant.
71
Chapter 5
72
Polymers
 Polymers in drug delivery systems can be produced by using natural or synthetic polymers,
which can be biodegradable or non-biodegradable.
 The polymers used in DDS should present a set of properties that make them suitable
materials to interact with the human body so the biodegradability is one of the most
important features.
 Biodegradable polymers are particularly attractive for application in DDS since, once
introduced into the human body, they do not require removal and their degradation products
are normal metabolites that can be easily cleared from the body.
73
Applications of Polymers
1)Polymers in Tableting
Tablet is kind of solid dosage form which is prepare by compressing therapeutically active
ingredient with pharmaceutical excipients.
1. Binders Methyl cellulose (Methocel), starch, gelatin,

PVP, EC and HPMC
2. Disintegrating Carboxymethyl cellulose PVP and sodium
CMC are use as super disintegrants.
3. Coating Agent Hydroxypropyl cellulose (HPC),
hydroxypropyl methylcellulose (HPMC)
4. Enhances Compressibility MCC enhances compressibility of tablet.
micro crystalline cellulose
2)Polymers in Capsule
Capsule shell Hard gelatin and soft gelatin.

Fillers MCC and starches are used to fill up the volume in capsule
3)Polymers in disperse system
 It is heterogeneous thermodynamically unstable liquid system in whichdrugs substances

either solid or liquid is disperse in dispersion medium.
 Examples of pharmaceutical dispersion system are suspensions, emulsions, creams,
ointments and aerosols.
 Alginates carrageenan and xanthan gum are naturally occurringdispersing agents, while
poly (acrylic acid), PVP, PVA and cellulose ethers are semisynthetic agents.
74
4) Polymers in gels
 Cross-linked gels are most commonly known as hydrogels.
 They are also known as smart polymers because they show different gelling properties
in different environment of water.
 Most commonly used hydrogels are poly (hydroxyethyl methacrylate), poly
(methacry1ic acid) and poly (acrylamide). In pharmaceutical industries cross-linked gels
are primarily use for local drug delivery of drugs to skin, oral cavity, vagina and rectum.
5) Polymers in transdermal drug delivery systems (patches)

 Transdermal drug delivery system generally use for delivery of therapeutic agent across
skin to systemic circulation.
 System has several applications in pain management, cessation of smoking, heart
diseases and hormonal replacement.
 In transdermal drug delivery system polymers are used as protective coverings and
adhesives.
 Adhesives used are acrylates, silicones and poly isobutylates
6) Polymers in ocuserts
 Ocusert is use in treatment of eye disorders like glaucoma.
 Ocusert is elliptical shape implant having several layers.
 Poly (ethylene-co-vinyl acetate) is used to prepare pilocarpin ocusert.
7) Polymers in progestasart system

 Progestasart intra-uterine device is the example of controlled drug delivery system
medicated implant use for contraceptive purpose.
75
 The drug release from progestasart occurs by diffusion polymer act as a rate controlling
membrane for drug release. Polyethylene and poly (ethyleneco-vinyl acetate) are used
in such system.
8) Polymers in nanoparticles
 Nanoparticles have size range of 10-1000nm. In nanoparticle drug delivary system
drug is attached, entrapped and dissolve to polymeric matrix.
 Polymeric nanoparticles are used for sustain drug delivery system.
 Both biodegradable and nonbiodegradable polymers are used. These biodegradable
polymers degrade into nontoxic and biologically active substances.
 Example of synthetic biodegradable polymers are poly lactide and poly-ɛ-
caprolactone.
9) Suture synthesis
 Both Biodegradable and non-biodegradable polymers are used
76
Chapter 6
77
Advanced therapy medicinal products

Advanced therapy medicinal products (ATMPs) are innovative therapies that
encompass gene therapy, somatic cell therapy, and tissue-engineered products.
Advanced therapy medicinal products (ATMPs) constitute an innovative class of
heterogeneous research driven biopharmaceuticals. This class encompasses gene
therapy medicinal products (GTMPs), somatic cell therapy medicinal products
(sCTMPs), tissue-engineered products (TEPs), and combined products (tissue or cell
associated to a device)
78
Biotechnology therapeutic products

Biotechnology
 It is the use of microorganisms, plants, animals or parts of them for the production
of useful compounds and pharmaceutical.
 Biotechnology is concerned as the biotechnological manufacturing of
pharmaceutical products.
Formulation of biotechnology products
A good formulation is a key factor for the success of a biological drug from beginning
to end, throughout the research and drug product development stages. Formulations
for biological molecules must be based on:
1. Understanding of the physical and chemical properties of the molecule itself,
Protein structure, conformation, chemical degradation and aggregation
studies in aqueous solutions at different pH values, temperatures, using
different buffers and in the presence of different ingredients (e.g. ions,
sugars, detergents)
2. An easy administration procedure,
3. Optimal release of the active protein at the administration site,
4. Optimal activity of the molecule at the target site,
5. Minimum side effects
6. Cost-effective manufacture of the formulation.
 The complexity of physical and chemical properties influences the stability of the
formulation, as well as the biological activity.
79
 This makes it difficult to formulate proteins using standard procedures, in a routine

process, with standard excipients.
 Since the formulation of proteins is difficult and unpredictable, these activities
often take many years, and not infrequently fail.
Formulation Considerations of Biopharmaceutical

1. Sterility
Most proteins are administered parenterally and it should be sterile (But are
sensitive to heat and other sterilization treatments) so cannot withstand
[autoclaving, gas sterilization, or sterilization by ionizing radiation].
Protein pharmaceuticals assembled under aseptic conditions, following established
and evolving rules in the pharmaceutical industry for aseptic manufacture.
2. Viral Decontamination
As recombinant DNA products are grown in microorganisms, these
organisms should be tested for viral contaminants and appropriate measures should
be taken if viral contamination occurs.
Excipients with a certain risk factor, such as blood derived human serum
albumin, should be carefully tested before use and their presence in the formulation
process should be minimized.
3. Pyrogen removal
Pyrogens are compounds that induce fever. Exogenous pyrogens (pyrogens
introduced into the body, not generated by the body itself) can be derived from
bacterial, viral or fungal sources. Bacterial pyrogens are mainly endotoxins shed
from gram negative bacteria. They are lipopolysaccharides.
80
Pyrogen removal of recombinant products derived from bacterial sources

should be an integral part of preparation process.Excipients used in the protein
formulation should be essentially endotoxins-free.
Pyrogen removal of recombinant products derived from bacterial sources

should be an integral part of preparation process.
Ion exchange chromatographic procedures (utilizing its negative charge)
can effectively reduce endotoxins levels in solution.For solutions, water for
injection (compendial standards) is (freshly) distilled or produced by reverse
osmosis.
4. Excipients Used in Parenteral Formulations of Biotech Product
In a protein formulation (active substance), a number of excipients selected
to serve different purposes. The nature of the protein (e.g. lability-rapid change or
destroyed-) and its therapeutic use (e.g. multiple injection systems) can make these
formulations quite complex in term of excipients profile and technology (freeze-
drying, aseptic preparation)
Components found in parenteral formulations of biotech products
1. Active ingredient
2. Solubility enhancers
3. Anti-adsorption and anti-aggregation agents
4. Buffer components
5. Preservatives and anti-oxidants
6. Lyoprotectants/ cake formers
7. Osmotic agents
8. Carrier system
81
1. Solubility enhancer Proteins, in particular those that are non-glycosylated, may have a
tendency to aggregate and precipitate. Approaches that can be used to enhance solubility
include: Selection of the proper pH and ionic strength conditions, Addition of amino
acids, such as lysine or arginine (used to solubilize tissue plasminogen activator, t-PA),
Addition of surfactants such as sodium dodecylsulfate, to solubilize non-glycosylate,
IL-2 (interleukin-2) can also help to increase the solubility.
2. Anti-adsorption and anti-aggregation agents: these agents (added to reduce

adsorption of the active protein to interfaces). Some proteins normally have hydrophobic
sites in the core structure. They tend to expose hydrophobic sites when an interface is
present. These interfaces can be water/air, water/container wall or interfaces formed
between the aqueous phase and utensils used to administer the drug (e.g. catheter,
needle). Ex: Albumin (strong tendency to adsorb to surfaces) and is therefore added in
relatively high concentration (e.g. 1%) as an anti-adhesion agent to protein formulations.
Mechanism: albumin competes with the therapeutic protein for binding sites and
prevents adhesion of the therapeutically active agent by combination of its binding
tendency and abundant presence.
3. Buffer components Buffer selection is an important part of the formulation process,
because of the pH dependence of protein solubility, physical and chemical stability.
Buffer systems regularly encountered in biotech formulations are: phosphate, citrate or
acetate buffer. Protein molecule is affected by pH of its surrounding environment and
can become more positively or negatively charged due to the gain or loss, of (H+).
temporary pH changes can cause aggregation. These conditions can occur, for example,
during the freeze-drying process, when one of the buffer components is crystallizing and
the other is not. In a phosphate buffer, Na2HPO4 crystallizes faster than NaH2PO4. This
causes a pronounced drop in pH during the freezing step. Other buffer components do
not crystallize, but form amorphous systems and then pH changes are minimized.
82
4. Preservatives and anti-oxidants

Anti-oxidants
Methionine, cysteine, tryptophane, tyrosine and histidine are amino acids that are
readily oxidized. Proteins rich in these amino acids are susceptible to oxidative
degradation. The replacement of oxygen by inert gases in the vials helps to reduce
oxidative stress. More-over, the addition of anti-oxidant such as ascorbic acid or sodium
formaldehyde sulfoxylate can be considered.
Ascorbic acid can act as an oxidant in the presence of a number of heavy metals.
Preservatives
Certain proteins are formulated in the container designed for multiple injection
schemes. After administering the first dose, contamination with microorganism may
occur and the preservatives are needed to minimize growth. Usually, these preservatives
are present in concentrations that are bacteriostatic rather than bactericide in nature.
Antimicrobial agents mentioned in the USP XXIV are the mercury-containing
pheylmercuric nitrate and thimerosal and p- hydroxybenzoic acids, phenol, benzyl
alcohol and chlorobutanol.
5. Osmotic agents
For proteins, the regular rules apply for adjusting the tonicity-of parenteral products.
Saline and mono- or disaccharide solutions are commonly used. These excipients may
not be inert; they may influence protein structural stability. For example, sugars and
polyhydric alcohol can stabilize the protein structure through the principle of
preferential exclusion. These additives enhance the interaction of the solvent (water
structure promoters) with the protein and are themselves excluded from the protein
surface layer; the protein is preferentially hydrated. This phenomenon can be monitored
through an increased thermal stability of the protein.
83
6. Lyoprotectants
Substance which protect drugs especially protein during freeze drying process.
Examples are sugars (mannitol, lactose, maltose, maltodextrin, sucrose) and aminoacids
(glycine, histadine, argenine). This is occur by two mechanisms
a. Water replacement theory: good stabilizer serve as a water substitute by
hydrogen bonding to the dried protein.
b. Verification theory : the protein and stabilizer are both amorphous glasses
immobilized together where the stabilizer protect the protein
Stability of Protein Based Pharmaceuticals

Protein can be stored
(1) As an aqueous solution,
(2) In freeze-dried form, and,
(3) In dried form in a compacted state (tablet) .
The stability of protein solutions strongly depends on factors such as pH, ionic
strength, temperature, and the presence of stabilizers.
Maintaining product stability during the various drug product process unit operations
is paramount to our ability to supply safe and efficacious biotech products to patients.
New technologies are helping us ensure that we meet these challenges successfully
the three of the significant technical challenges experienced in drug product
manufacturing, namely
1. Maintaining product stability during frozen storage,
2. Performing visual inspection of drug product vials,
3. Controlling protein particulates.
84
1. Maintaining product stability during frozen storage

The simplest storage method involves filling the bulk solution into bottles of appropriate
size and storing in freezers. These containers are often made of polyethylene or
polypropylene, although steel can be used for small volumes.
Their advantage is simplicity. Disadvantages include a lack of active control and potential
variability between containers, as well as multiple container–closures to secure against
contamination. The procedure for preparation, loading, and placement in the freezer has
to be well defined to reduce this variability. Thawing is generally performed by placing
containers in a refrigerator or at room temperature.
2. Automated visual inspection
Various light transmission or camera-based commercial systems are currently available in
the market and can be used to perform automated visual inspection (AVI) of sterile drug
products. The automated inspection machine (AIM) used in this study uses a light
transmission–based static division system to detect particles of foreign contaminants in
vials filled with liquid product.
3. Particulates in biopharmaceutical formulation
Particles may be generated as a result of large-scale manufacture or because of an inherent
property of the protein molecule. The large-scale manufacturing of protein drug products
involves processing steps such as purification, formulation, freeze– thaw, filling, shipping,
and storage. Stresses that are introduced during these steps can cause instabilities that can
lead to aggregation and particulation.
85
Subject Page No.
Introduction 1
Course specification 2
Chapter 1: Preformulation 12
Chapter 2: Targeted drug delivery systems 27
Chapter 3: Nano-sized drug delivery systems 38
Chapter 4: Implants 68
Chapter 5: Polymers 72
Chapter 6: Biotechnology Therapeutic Products 77
86

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Mansoura University

((Pharm D( – ‫بكالوريوس الصيدلة ( فارم دى‬

Academic Level: Level 5 ‫ الخامس‬: ‫المستوى األكاديمي‬

Scientific department: Pharmaceutics ‫ الصيدالنيات‬: ‫القسم العلمي‬

Head of Department: : ‫رئيس القسم‬

Course Coordinator: : ‫منسق المقرر‬

A. Basic Information: Course data:

Course Title Advanced Drug Delivery Systems

Domain 2: professional and ethical practice

Domain 4: personal practice:

4. Teaching and Learning Methods:

6. Facilities required for teaching and learning

8. Matrix of knowledge and skills of the course

Mechanisms of targeting and strategies ✔ ✔

Course contents / Domain 1 Domain 2 Domain 4

Targeted Drug Delivery Strategies ✔ ✔ ✔

9. Matrix between course contents and methods of learning and assessment

Polymers (synthetic polymers) √ √ √ √

Course Coordinator Prof. Dr. Marwa Salah El-Din El-Dahhan

Head of Department Prof. Dr. Irhan Ibrahim Abu Hashim

2. Cohesion between one particles to another.

 Why inter-particle cohesion is found: it may be due to existence of non-specific Vander

 θ > 50º implies unsatisfactory flow behaviour.

• Density and Porosity

 By particle size enlargement

 By densification with the help of slugging (dry granulation)

 By removing static charge

 Using auger feed equipment, mainly to produce a continuous dosing flow.

 By addition of flow activator. E.g., MgO

 By altering process condition like vibration assisted hopper or forced feeder

Compression behavior study

 Also known as Carr's index.

CARR’S INDEX (%) = (TAPPED DENSITY – POURED DENSITY) X 100

Relationship between powder flowability and % compressibility

NO % Compressibility range Flow descriptions

1 5-15 Excellent (free flowing granules)

2 12-16 Good (free flowing powder granules)

3 18-21 Fair to passable (powder granules

4 23- 28 Poor (very fluid powder)

5 28-35 Poor (fluid cohesive powder)

6 35-38 Very poor (fluid cohesive powder)

7 >40 Extremely poor (cohesive powder)

Depending on the compression characteristics type of material may be:

• But plastic material will get bonding after Viscoelastic deformation.

• Elastic material may lead to capping & lamination.

• They require wet massing to induce plasticity or plastic tableting material.

4. Punch Filming [Sticking]:

• If elastic material  By plastic tableting material, Wet granulation, Pre compression.

(a) True density

• It’s basically determined by displacement method utilizing either an insoluble solvent

𝐴𝑝𝑝𝑎𝑟𝑒𝑛𝑡 𝐵𝑢𝑙𝑘 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 = 𝑊𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑜𝑤𝑑𝑒𝑟/𝐵𝑢𝑙𝑘 𝑣𝑜𝑙𝑢𝑚𝑒

• It is calculated as ratio of volume of voids: total volume. It lies between 0 and 1.

𝑃𝑜𝑟𝑜𝑠𝑖𝑡𝑦 = 𝑉𝑜𝑖𝑑 𝑣𝑜𝑙𝑢𝑚𝑒 / 𝐵𝑢𝑙𝑘 𝑣𝑜𝑙𝑢𝑚𝑒

(C) Determination of viscosity

• Falling sphere viscometer

• Cup and bob viscometer

• Cone and plate viscometer

• Brook field viscometer

• Ultrasonic Shear Rheometer: For analyzing protein solution rheology.