controlled release drug product

2. BIOPHARMACEUTICAL &
PHARMACOKINETIC CONSIDERATIONS IN
DEVELOPMENT OF CONTROLLED RELEASE
DRUG PRODUCT

3. LARAIB JAMIL
REGISTERED M-PHILL SCHOLAR
DEPARTMENT OF PHARMACEUTICS
UNIVERSITY OF BALOCHISTAN

5. BIOPHARMACEUTICS
 Biopharmaceutics is the study of the interrelationship of
the physical/chemical properties of the drug, the dosage
form (drug product) in which the drug is given, and the
route of administration on the rate and extent of systemic
drug absorption.
[accesspharmacy.mhmedical.com]

6. PHARMACOKINETICS
 Pharmacokinetics, sometimes described as what
the body does to a drug, refers to the movement of
drug into, through, and out of the body—the time
course of its
absorption, bioavailability, distribution, metabolis
m, and excretion.
[www.msdmanuals.com/professional/clinical-]

8. DRUG PRODUCT
 (1) A dosage form that contains an active drug ingredien
t or placebo.
(2) A finished dosage form of a therapeutic gent as
described in regulations.
[medical-dictionary.thefreedictionary.com]

9. CONTROLLED RELEASE DRUG DELIVERY
It is
 Controlled rate
 Localized drug action
 Target drug action.

10. WHY WE GO TOWARDS CONTROLLED
RELEASE DRUG DELIVERY ?

11. ADVANTAGES
 Improves patient convenience
 Reduction in fluctuation in steady state level.
 Increse the safety margin of high potency drug
 Reduction in total health care cost

12. DISADVANTAGES
 Decreases systemic availability
 Poor invitro invivo corelation
 Increased risk of toxicity
 Retrieval of drug is difficult in toxicity, poisoning or
hyper senstivity reaction.

13. MECHANISM/PHARMACEUTICAL ASPECTS OF
CONTROLLED RELEASE DELIVERY (ORAL)
 Dissolution:
1. Matrix
2. Encapsulation
 Diffusion :
1. Matrix
2. Reservoir
 Combination of both dissolution and diffusion

14. • OSMOTIC PRESSURE CONTROLLED SYSTEM

15. DISSOLUTION
 Dissolution is when solid substance dissolves in a
solvent
 Mass transfer from solid to liquid
 Rate determining step : Diffusion from solid to liquid
[biopharmaceutics and pharmacokinetics D.M Brahmankar,
Sunil.Jeswal]

16. DIFFUSION
 Diffusion occurs when particles spread. They move
from a region where they are in high concentration to a
region where they are in low concentration. Diffusion
happens when the particles are free to move
[ BBC-GCSE Bitesize Difffusion]

18. MATRIX DIFFUSION TYPE
 Rigid matrix diffusion:
Materials used are insoluble plastics such as PVP
and fattyacids
 Swellable matrix diffusion:
1. Also called galaxy hydrogels popular for
sustaining the release of highly water soluble
drugs .
2. Materials used are hydrophilic gums.

19. SWELLABLE MATRIX DIFFUSION

20. RESERVOIR SYSTEM
 Also called laminated matrix device.
 Hollow system contaning
an inner core surrounded
in water insoluble
membrane.
 Polymer can be applied
by coating or
microencapsulation.
 Rate controlling mechanism-
partitioning into membrane with
subsequent release into surrounding
fluid by diffusion.

21. RESORVOIR SYSTEM
 Commonly used polymers : ethyl cellulose polyvinyl
acetate
 Example: transdermal patch
[the eastern pharmacist, november 1993
Sustained release drug V.R Gudsoorkar & D.Rmbhau]

23. COMBINATION OF DISSOLUTION & DIFFUSION

24. OSMOTIC PRESSURE CONTROLLED SYSTEM
 Osmosis: movement of particles/solvent from lower
to high concentration.
 The passage of solvent from in the solution through
semipermeable membrane
 Osmotic pressure: it is hydrostatic pressure
produced by a solution in a space devided by a
semipermeable membrane due to difference in
conc of solutes.

25. OSMOTIC PRESSURE CONTROLLED SYSTEM
 Provides zero order release
 Drug may be osmotically active or combined may
be osmotically salt (e.g NaCl)
 Semipermeable membranes usually made up of
cellulose acetate
 More suitable for hydrophilic drugs
 Procardia XL (ca channel blocker)
[novel drug delivery system vol-50 W.Y Chien]

26. OPCS
1. 2 compartments separated by moveable partition
2. Osmotically active compartment absorbs water
from GIT
3. Create osmotic pressure
4. Partition move upword and drug releases

28. PARENTERAL CONTROLLED RELEASE DRUG
DELIVERY SYSTEM
 The Parenteral administration route is the
most common and efficient for delivery of
active drug substances with poor bio-
availability and the drugs with a narrow
therapeutic index.
 Drug delivery technology that can reduce
the total number of injection throughout the
drug therapy period will be truly
advantageous not only in terms of
compliance, but also to improve the quality
of the therapy and also may reduce the
dosage frequency.
[A Review on Parenteral Controlled Drug Delivery System
Pravin Ghagare*1, Vandana Patel1, Rohit Gosavi1, Yogesh Thengal1 ]

29. MAJOR ROUTES OF PARENTERAL ADMINISTRATION
 � Intravenous (into a vein).E.g., Total parenteral
nutrition (TPN)
 � Intra-arterial (into an artery).E.g. Vasodilator drugs in
the treatment of vasospasm and thrombolytic drugs for
treatment of embolism.
 � Intramuscular (into a muscle).E.g. Many vaccines,
Antibiotics and Long-acting Psychoactive Agents
 � Intracardiac (into the heart).E.g. Adrenalin during
cardiopulmonary resuscitation (not commonly performed
anymore).

30. MAJOR ROUTES OF PARENTERAL ADMINISTRATION
 SUBCUTANEOUS
Adipose and connective tissues are poorly perfused
with blood. This route is generally limited to non-
irritating, water-soluble drugs that are well
absorded, e.g., insulin. The volume of
subcutaneous injection is usually restricted to 0.5-
1.5 ml.
 INTRA PERITONEAL
(Within peritoneum) Lymphatic channel are
frequently the route by which tumor metastasize
micro molecules administer intraperitoneally can
gain access to the lymphatic system and return
slowly to the vascular compartment. Thus, a
macromolecule may be used as a carrier to
target Antineoplastic agents into the lymphatic

31. ADVANTAGES
 Improved patient convenience and compliance.
 � Reduction in fluctuation in steady-state levels.
 � Increased safety margin of high potency drugs.
 � Maximum utilization of drug.
 Reduction in health care costs through improved
therapy, shorter treatment period, less frequency of
dosing

32. DISADVANTAGES
 Danger of device failure
 � Limited to potent drug
 � Decreased systemic availability
 � Possibility of dose dumping.
 � Retrieval of drug is difficult in case of toxicity,
poisoning or hypersensitivity reactions.
 � Higher cost of formulations.

33. PARENTERAL NOVEL DRUG DELIVERY SYSTEM
 INJECTABLES
 Both aqueous as well as oil solutions may be used
for parenteral controlled drug release. With
aqueous solutions (given i.m.), the drug release
may be controlled by increasing the viscosity of
vehicle by use of MC, CMC, or PVP and thus,
decreasing molecular diffusion and localizing the
injected drug.

34. INJECTABLES
 Oil solutions control the release by partitioning the
drug out of the oil in the surrounding aqueous
biofluids. Vegetable oils like arachis oil, cottonseed
oil, etc are used for such a purpose. The method is
applicable only to those drugs which are oil-soluble
and have optimum partition coefficient.

35. COLLOIDAL DISPERSION
 Liposomes :
 Liposomes are formed by the self-assembly of
phospholipids molecules in an aqueous
environment. The amphiphilic phospholipid
molecules form a closed bilayer sphere in an
attempt to protect their hydrophobic groups from
the aqueous environment while still maintaining
contact with the aqueous phase via the hydrophilic
head group.

36. LIPOSOMES

37. LIPOSOMES
 Liposomes interact with cell membrane by-
1. Fusion-the lipid portion of the vesicle-fuses with
cell membrane and contents of the vesicle are
released into the cell.
2. Endocytosis-cell engulfs the vesicle and lyses, it
releasing the contents.
3. Adsorption-vesicle is adsorbed on the surface of
cell membrane and its content diffuses into the cell.

38. ACCEPTANCE OF LIPOSOMES BY CELL

39. APPLICATION OF LIPOSOMES
 Liposomal Anti-Cancer Agent: Liposomal
doxorubicin is now licensed as Caelyx for the
treatment of Kaposi's sarcoma.
 � Liposomal Anti-Infective Agents: Liposomal
amphotericin B (Ambisome) is used for the
treatment of systemic fungal infection.
 � Liposomes as Vaccine Adjuvants: Liposomal
vaccines can be made by associating microbes,
soluble antigens, cytokines, or DNA with liposomes,
the latter stimulating an immune response on
expression of the antigenic protein
. [ A Review on Parenteral Controlled Drug Delivery System
Pravin Ghagare*1, Vandana Patel1, Rohit Gosavi1, Yogesh Thengal1 ]

40. NIOSOMES
 Niosome are non-ionic
surfactant vesicles
obtained on hydration of
synthetic nonionic
surfactants, with or
without incorporation of
cholesterol or their lipids.

41. APPLICATIONS OF NIOSOMES
 Anticancer Niosomes: It accumulates within tumors.
For example, niosomal encapsulation of
doxorubicin and methotrexate increases drug
delivery to the tumor and tumoricidal activity.
 � Niosomes at Targeted Site: Uptake by the spleen
and liver make niosomes ideal for targeting
diseases. For example leishmaniasis and the
niosomal formulations of sodium stibogluconate
improve parasite suppression in the spleen, bone
marrow. and liver.
 � It is also used in depot systems for short-acting
peptide drugs on intramuscular administration.
 � Niosomes used in Ophthalmic drug delivery

42. NANOPARTICLES
 Nanosuspension
 Nanosuspensions of drugs are submicron colloidal
produced by suitable methods and stabilized by
surfactants. A pharmaceutical nanosuspension can
be defined as the Nano-sized drug particle which is
finely dispersed in an aqueous vehicle for either
oral and topical use or parenteral and pulmonary
administration. In general, the particle size in
nanosuspension is always (usually lies between
200nm to 600nm)

43. NANOPARTICLES
 Application of nanosuspension :
 Nanosuspension can be delivered either
intravenous route or intra-articular. But in case of
parenteral administration, solute should be
remained in solubilized form or particle or globule
size below 5mm to avoid capillary blockage.
 Some current approaches have come resolve the
drawbacks of poorly soluble drug for parenteral
delivery. These are salt formation, Solubilization
using co-solvent, complexation with cyclodextrin
and vesicular system (liposome and
transferosome).
 for example, paclitaxel nanosuspension has been
found better responses in treating tumour than
taxol.

44. NANOEMULSION/MICROEMULSION
Nanoemulsion / Microemulsion are liquid dispersions
of water and oil that are made homogenous,
transparent (or translucent) and thermodynamically
stable by the addition of relatively large amounts of
a surfactant and a co-surfactant and having
diameter of the droplets in the range of 100 � 1000
A (10 �- 100 nm)
[ A Review on Parenteral Controlled Drug Delivery System
Pravin Ghagare*1, Vandana Patel1, Rohit Gosavi1, Yogesh
Thengal1 ]

45. APPLICATIONS OF MICROEMULSION
 Microemulsions used as intravenous delivery
systems for the fat soluble vitamins and lipids in
parenteral nutrition.
 � O/W Microemulsions were characterized by their
small particle size and their wide range of
temperature stability, typically from about 200�-
500C.
 They could be administered by intravenous,
intraocular, intraarticular, intraperitoneal and
intramuscular.

46. MICROPARTICLES
 Microsphere : Microspheres are small spherical
particles, with diameters in the micrometer range
(typically 1 mm to 1000 mm). Microspheres can be
manufactured from various synthetic and natural
materials. Polymer microspheres, ceramic
microspheres and Glass microspheres are
commercially available.
 Solid microspheres have numerous applications
depending on what material they are constructed of
and what size they are. Hollow microspheres are
typically used to lower the density of a material.

47. RELEASED ERYTHROCYTES
 Drug loading can be done by immersing the cell in
buffered hypotonic solution of drug which causes
them to rupture and release hemoglobin and trap
the medicament. On restoration of isotonicity and
incubation at 370C, the cells reseal and are ready
for use upon reinjection; the drug loaded
erythrocytes serve as slow circulating depots.

48. RELEASED ERYTHROCYTES
 Advantages :
 Fully biodegradable, biocompatible, and non
immunogenic.
 � Longer life span in circulation.
 � Protection of the drug from enzymatic
inactivation.

49. RELEASED ERYTHROCYTES
 Applications:
 Damaged erythrocytes are rapidly cleared from
circulation of phagocytic Kupffur cells in liver and
spleen.
 � Treatment of parasitic diseases: Antimalarial,
antileishmanial and antiamoebic drugs
(METRONIDAZOLE, TINIDAZOLE) can be
delivered.

50. IMPLANTS
 Lafarge first introduced the concept of implantable
therapeutic system for long term, continuous drug
administration in 1861 with the development of a
subcutaneous implantable drug pellet.
 The technique was used to administered crystalline
hormone in form of solids steroids pellets. Implant
represents novel approach in the use of solid
dosage forms as parenteral product.

51. IMPLANTS
 Implants are insert under the skin by cutting and
stitching it alter insertion of' the sterile tablet which
is cylindrical, rod and ovoid shaped and more than
8 mm in length. The sterile tablets consisting of the
highly purified drug, compressed without excipients.
If, intended for subcutaneous implantation in the
body.
[ A Review on Parenteral Controlled Drug Delivery
System
Pravin Ghagare*1, Vandana Patel1, Rohit Gosavi1,
Yogesh Thengal1 ]

52. IMPLANT

53. CLASSIFICATION OF INJECTABLE IN SITU FORMING
IMPLANTS:
 THERMOPLASTIC PASTES :
 Semi-solid polymers can be injected when melted
and form a depot upon cooling to body
temperature.
 The requirements for such In Situ Forming Devices
(ISFD) include low melting or glass transition
temperatures in the range of 250C to 658�C and
an intrinsic viscosity in the range of 0.05 to 0.8 dl/g.
 Thermoplastic pastes allow local drug delivery at
sites of surgical interventions for the delivery of
antibiotic or cytotoxic agents. Alternatively, they can
be used to generate a subcutaneous drug reservoir
from which diffusion occurs into the systemic

54. 2-) THERMALLY INDUCED GELLING SYSTEMS:
 Numerous polymers show abrupt changes in
solubility as a function of environmental
temperature.
 MacroMed distributes OncoGelw, which contains
paclitaxel at a concentration of 6 mg/g ReGelw for
intratumoral injection, followed by a continuous
drug release over a period of 6 weeks.
 The clear advantage is the ability to solubilize the
water-insoluble drug substances, such as
paclitaxel, which allows a prolonged release for
more than 50 days.

56. SOLID IMPLANTS
 Implants are cylindrical, monolithic devices of mm
or cm dimensions, implanted by a minor surgical
incision or injected through a large bore needle into
the S.C or I.M tissue.
 Subcutaneous tissue is an ideal location because
of its easy access to implantation, poor perfusion,
slow drug absorption and low reactivity towards
foreign materials.
 The drug in implant may be dissolved, dispersed or
embedded in a matrix of polymer or waxes/lipids
that control release by dissolution and/or diffusion,
bioerosion, biodegradation or an activation process
such as osmosis or hydrolysis.

57. INFUSION DEVICES
These are also implantable devices but are
versatile in the sense that they are
intrinsically powered to release the
medicament at a zero-order rate and the
drug reservoir can be replenished from
time to time. Depending upon the
mechanism by which these implantable
pumps are powered to release the contents

58. EXAMPLE INCLUDE:
 An infusion pump is a
medical device that delivers fluids,
such as nutrients and medications,
into a patient's body in controlled
amounts. Infusion pumpsare in
widespread use in clinical settings
such as hospitals, nursing homes,
and in the home.

59. INFUSION DEVICES
They are classified into following
types:
1. Osmotic pressure activated drug
delivery systems
2. Vapour pressure activated drug
delivery systems
3. Battery powered drug delivery
systems

60. OSMOTIC PRESSURE ACTIVATED DRUG DELIVERY
SYSTEM
 Alzet Osmotic Pump 10/pk. ALZET pumps are
miniature(small) delivery systems designed to
provide constant, accurate administration of test
agents.
[www.braintreesci.com]

62. ALZET OSMOTIC PUMP
 The ALZET pumps are capsuler in shape and made
in variety of sizes and provide zero order delivery of
drug.
 The pump is made of three layers as shown in
figure.
 1) The innermost drug reservoir contained in a
collapsible impermeable polyester bag (which is
often to the exterior via a single portal).

63. ALZET OSMOTIC PUMP
2) An intermediate sleeve of dry osmotic energy
source (sodium chloride).
3) The outermost rigid, rate controlling from
substituted cellulosic polymers.

64. ALZET OSMOTIC PUMP
1. An additional component that flow modulator,
comprising of a cap and a tube made of stainless steel
is inserted into the body of osmotic pump after filling.
2. After implantation, water from the surrounding tissue
fluids is imbibed at a controlled rate that dissolves the
osmagent creating an osmotic pressure differential
across the membrane.
3. The osmotic sleeve thus expands and since the outer
wall is rigid, it squeezes the inner flexible drug
reservoir and the drug solution is expelled in a
constant volume per unit time fashion.
4. The drug delivery continues until the reservoir is
completely collapsed. Ionized drugs, macromolecules,
steroids and peptides (insulin) can be delivered by
such a device.

65. DUROS INFUSION IMPLANT
 The DUROS osmotic implant is a non-
biodegradable, miniature titanium
cylinder intended to enable systemic or
tissue specific therapy for small molecule
drugs, peptides, proteins, DNA and other
bioactive macromolecules.
 The implant, which is inserted
subcutaneously and retrieved at the end
of the treatment duration, is designed to
precisely and continuously deliver drugs
for periods ranging from one month to
more than a year e.g. leuprolide acetate
implant (for prostate cancer).

66. DUROS INFUSION IMPLANT
 The outer titanium alloy cylinder is capped by a
semipermeable membrane at one end and by an
exit port at the other end. Within the cylinder are an
osmotic engine, a piston and the drug reservoir.
When the DUROS system is implanted in the body,
water from surrounding tissue enters one end of the
cylinder and the osmotic engine to swell which
leads to release of the drug.

68. VAPOUR PRESSURE POWDERED PUMP
 This device on the principle that at a given
temperature, a liquid in equilibrium with its vapour
phase exerts a constant pressure that is
independent of enclosing volume. The disc shaped
device consists of two chambers an infusate
chambers containing the drug solution, which is
separated by a freely movable flexible bellow from
the chamber containing inexhaustible vaporizable
fluid such as fluorocarbons.

69. VAPOUR PRESSURE POWDERED PUMP
 After implantation the volatile liquid vaporizes at the
body temperature and creates a vapour pressure
that compresses the bellows and expels the
infusate through a series of flow regulators at a
constant rate. Morphine for terminally ill cancer
patients and Insulin for diabetics have been
successfully delivered by such a device.
[ A Review on Parenteral Controlled Drug Delivery System
Pravin Ghagare*1, Vandana Patel1, Rohit Gosavi1, Yogesh
Thengal1 ]

71. BATTERY POWERED PUMPS:
 Two types of battery powered
implantable ,programmable pumps
used successfully to deliver insulin
are peristaltic pumps and solenoid
driven reciprocating pumps both
are with electronic controls. Design
is such that the drug moves
towards the exit and there is no
backflow of the infusate.

73. CONTACT LENSES AS DRUG CONTROLLED RELEASE
SYSTEMS
 Topically applied therapy is the most common way to
treat ocular diseases, however given the anatomical and
physiological constraints of the eye, frequent dosing is
required with possible repercussions in terms of patient
compliance.
 Beyond refractive error correction, contact lenses (CLs)
have, in the last few decades emerged as a potential
ophthalmic drug controlled release system (DCRS).
 Extensive research is underway to understand how to
best modify CLs to increase residence time and
bioavailability of drugs within therapeutic levels on the
ocular surface.
[a narrative review: Rev. bras.oftalmol. vol.75 no.3 Rio de
Janeiro May/June 2016 ]

74. CONTACT LENSES AS DRUG CONTROLLED RELEASE
SYSTEM
 These devices may simultaneously correct ametropia
(an abnormal refractive condition of the eye in which
images fail to focus upon the retina) and have a role in
managing ophthalmic disorders that can hinder CL wear
such as dry eye, glaucoma, ocular allergy and cornea
infection and injury.
 In this narrative review the authors explain how the
ocular surface structures determine drug diffusion in the
eye and summarize the strategies to enhance drug
residence time and bioavailability.
 They synthesize findings and clinical applications of
drug soaked CLs as DCRS combined with delivery
diffusion barriers, incorporation of functional monomers,
ion related controlled release, molecular imprinting,
nanoparticles and layering.

75. CONTACT LENSES AS DRUG CONTROLLED RELEASE
SYSTEM
 these novel ophthalmic agents
delivery systems in improving
drug transport in the target
tissue and patient compliance,
in reducing systemic absorption
and undesired side effects, and
discuss future perspectives.

76. FACTORS CONSIDERATIONS IN CRDD

77. FACTORS CONSIDERATION IN CRDD
 Selection of drug candidate
 Medical rationale
 Biological factors
 Physico-chemical properties
 In vitro analysis
 Formulation optimization
 In vivo data generation
[chein Y.W Novel drug delivery system edition: 2009]

78. 1-SELECTION OF DRUG CANDIDATE
 Neither very short nor very long half life
 No significant first pass metabolism
 Good absorption through GIT tract
 Highly soluble
 Minimize large no. doses
 Wide therapeutic window

79. 2-MEDICAL RATIONLE
 Frequency of dosing
 Patient complience
 Drug intake
 Fluctuation in serum conc
 Reduced side effects
 Sustained efficacy

80. 3-BIOLOGICAL RATIONALE
 Absorption
 Distribution
 Elimination
 Dose dependent bioavailability
 Drug protein-binding
 Half life (duration of action)
 Margin of safety
 Disease condition

81. 4- PHARMACO-KINETIC/DYNAMIC CONSIDERATIONS
 Dose dumping
 First pass metabolism
 Enzyme induction/inhibition upon multiple dosing
 Prolonged drug absorption
 Variability in GI emptying & motility

82. 5-PHYSICO CHEMICAL CONSIDERATIONS
 Solubilty & pKa
 Partition coefficient
 Molecular size & diffusivity
 Dose size
 Complexation
 Ionization constant
 Drug stability
 Protein binding

83. PHYSICO CHEMICAL FACTORS EFFECTING
CRDD

84. SOLUBILITY & PKA
 The solubilty of solid substance is defined as
‘’the conc at which solution phase in equilibrium
with a given solid phase at a steady state , temp &
pressure ‘’
 To improve solubilty we go towards
 Solvation
 Hydration
 Complexation
 Recrystalization
 Co-solvation
 surfactants

85. SOLUBILTY & PKA
 Absorption of poorly soluble drugs is often
dissolution rate limited.
 Such drugs don’t require any further control & thus
may not seen as good candidate for oral controlled
release formulation

86. PARTITION COEFFICIENT

87. PARTITION COEFFICIENT
 The partition coefficient is defined as ‘’the conc ratio
of unionized drug distributed b/w 2 phases at
equilibrium
 The apparent partition coefficient can be
1. Acidic
2. Basic
 Drugs that are very lipid soluble or very water
soluble, will be extreme in p.coeffecient

88. PARTITION COEFFICIENT
 Low (acidic/basic) slow flux into the tissues
 High(acidic/basic) rapid flux followed by
accumulation in tissue
Both cases are undesireable for CRDD

89. MOLECULAR SIZE & DIFFUSIVITY

90. MOL SIZE & DIFFUSIVITY
 In addition to diffusion through a variety of
molecular membranes, drugs in CRDD must diffuse
through a rate cantrolling membrane/matrix
 An important influence of difusivity in polymers is
the mol size of diffusing species
 Mol.size can be determined by MS (mass
spectroscopy) or FTIR (fourier transform IR)
 Diffusion (MATRIX/ENCAPSULATION) is rate
determining step in CRDD

91. DOSE SIZE

92. DOSE SIZE
 Size of drug play a major role in determining the
size of final finished product
 In case, the dose already high , then formulating
same in CRDD will further increase the overall
dosage size & there by reduce patient complience
NOTE: for drugs with an elimination half life of less
than 2 hours as well those which are administerd in
large dose are prohibited in CRDD

93. COMPLEX FORMATION

94. COMPLEXATION
 A method to entrap within a complexing agent like
cyclodextrin complex
 These complex could be helpful in entrapping drugs
of very high molecular weight which have low
diffusivity through the membrane
 This property facilitates increasing the solubility of
drug in required solvents.

95. IONIZATION CONSTANT

96. IONIZATION CONSTANT
 An ionization constant (using the symbol K) is a
constant that depends upon the equilibrium
between ions and molecules that are not ionized in
a solution or liquid. It is the ratio between the
product of concentration and reactant. Any
imbalance in the equation can lead to corrosion.
 An ionization constant is also known as a
dissociation constant.
[www.corrosionpedia.com]

97. IONIZATION CONSTANT
 From the site of release of drug its absorption
depends upon its ionization constant
 And it has been stated that drugs in unionized form
are absorbed faster than ionized species.

98. DRUG STABILITY

99. DRUG STABILITY
 Most oral controlled release system are designed to
release their contents over much of the length of GI
tract
 For drugs those are
1. Unstable in intestinal environment
2. Unstable in stomach environment
Might be difficult in formulate prolong release systm
to counteract such problems several modified
release methods are available that restrict the
release at GI site.

101. PROTEIN BINDING
 It refers the formation of complexes with the blood
protein (albumin) with the absorbed drug.
 This complex leads to
1. Inhibition of therapeutic effects of such amount
2. Half life is increased (compared to invitro studies)
3. Toxicity profile elevated
4. Mostly drugs (95%) are protein binding.
So this property is undesireable in CRDD
[overview of controlled release mechanism 2012
Siegel R A & Rathbone M]

102. INVITRO ANALYSIS
 The aim of this in-vitro experimental study was to
design a novel drug delivery system that may
permit controlled release of N-acetylcysteine (NAC)
following intratympanic administration(hearing
organs in animals).
 The system was composed of two different
solutions that attained a hydrogel form within
seconds after getting into contact with each other.
 The authors performed swelling, pH and
temperature tests and analysis of controlled release
of NAC from this novel controlled release system.
[a preliminar report: Ciftci Z1, Deniz M2, Yilmaz I3, Ciftci HG4, Sirin
DY5, Gultekin E2 2015 nov ]

103. FORMULATION OPTIMIZATION
 To formulate and optimize the formulation on the basis
of in vitroperformance of microsphere. A full factorial
design was employed to study the effect of independent
variables, polymer-to-drug ratio and stirring speed ,on
dependent variables, encapsulation efficiency, particle
size, and time to 80% drug release.
 Suppose the best batch exhibited a high entrapment
efficiency of 70% and mean particle size 290 μm. The
drug release was also prolonged for more than 12
hours. The study helped in finding the optimum
formulation with excellent prolong drug release.
[Sanjay Dey,1 Soumen Pramanik,1 and Ananya
Malgope2 research article volume 2011 ]