Ndds 1 classification of crdds part 3

Project date 20/09/2013
Al Ameen College
of Pharmacy
BY:
SURAJCHOUDHARY
M.PHARM (PHARMACEUTICS)
DEPT. OF PHARMACEUTICS
CONTROLLED RELEASE DDS
PREPARED BY:
PROF. SHASHANK CHAURASIYA
BANSAL COLLEGE OF PHARMAY, BHOPAL

Ppt. package
RECAP
FACTORS(Listed)
Dissolution Controlled DDS
DiffusionControlled DDS
References
Recent Trends
2

FA C T O R S
AFFECTING THE DESIGN OF CRDDS
3

FACTORS Consideration
FOR
CRDDSDesign
o Selectionofdrugcandidate
o Medical Rationale
o Biological Factors
o Physico-Chemical Properties
o Invitroanalysis
o Formulation optimization
o Invivodata generation
o Discussionwith Regulatory Authorities
o Data submission to RegulatoryAuthorities
for Marketing,Authorization / Approval. 5

SELECTION OF Drug Candidate
 Very short or very long half-life X
 Significant first pass metabolism X
 Poorabsorption throughout the GItract X
 Lowsolubility X
 Largeno. ofdose X
 Narrowtherapeutic window X
5

MEDICAL : Rationale
 FrequencyofDosing
 Patient compliance
 Drug intake
 Fluctuation ofserum concentration
 Reducedside effect
 Sustained efficacy
6

BIOLOGICAL Rationale
 Absorption
 Distribution
 Elimination
 Dose Dependent Bio-Availability
 Drug -ProteinBinding
 Duration ofAction(Half–life)
 MarginofSafety
 Disease Condition
7

PHARMACO-KINETIC/DYNAMIC
Considerations
 Dose Dumping
 First Passmetabolism
 EnzymeInduction/Inhibition upon multipledosing
 Variabilityofurinary pHeffect on drug elimination
 Prolonged drug absorption
 Variabilityin GIEmpting andmotility
8

PHYSICO-CHEMICAL Considerations
 Solubility&pKa
 Partition Coefficient
 MolecularSize&
Diffusivity
 Dose size
 Complexation
 Ionization Constant
 Drug stability
 Protein Binding
9

ORDER OF REACTION - a review
 Zero Order Release: Delivery rate remains
constant until device is exhausted of active
agent.
 First Order Release: Release is directly
proportional to amount of drug loaded in
device.
 Square-root-of-time(t-1/2) Release: Release
that is linear with reciprocal of square root of
time.(release rate remains finite even after
deviceapproaches exhaustion)
dMt/dt = k
Mt – Mass of drug
K – Rate constant
t - time
dMt/dt = k(M0 - Mt)
Mt – Mass of drug
M0 – Initial mass of drug
K – Rate constant
t - time
dMt/dt = k t1/2
Mt – Mass of drug
K – Rate constant
t - time
11

P H Y S I C O - C H E M I C A L
FA C T O R S
AFFECTING THE DESING OF CRDDS
11

SOLUBILITY & pKa
13
• The solubility of a solid substance is defined as…….
“ the concentration at whichthe solution phase isin equilibrium
with a givensolidphase at a stated temperature &pressure.”
• Toimprovesolubility:
Solvation Complexation
Hydration Recrystallization
Co-solvation Useofsurface active agents
• NOTE: A classification is given as per the permeability & solubility
profile,knownas BCSClassification.

SOLUBILITY & pKa
14
• Determination ofsolubility:
1. Semi-quantitative method
2. Accurate-quantitative method
3. pH-change method

SOLUBILITY & pKa
• Absorption of poorly soluble drugs is often dissolution rate-limited.
• Such drugs do not require any further control over their dissolution rate
and thus may not seem to be good candidates for oral controlled release
formulations.
• Controlled release formulations of such drugs may be aimed at making
their dissolution more uniform rather than reducing it.
15

PARTITION COEFFICIENT
17
• The partition coefficient is defined as…….
“ the concentration ratio of unionized drug distributed between
two phases at equilibrium.”
• Givenbythe Noyes-Whitney’sEquation:
P = [𝐴]𝑜/([𝐴]∞)
• The logarithm (base 10) of the partition coefficient (log10P) is often
used.

18
• For ionizable drugs, where the ionized species does not partition into the
organic phase, the APPARENTpartition coefficient, (D), can be calculated
as:……….
Acids:log10D=log10P– log10(1+10(pH-pKa))
Bases :log10D=log10P– log10(1+10(pKa-pH))
• The octanol-water partition coefficient, (log10Pow), has been widely used as
a measurement for determining the relative lipophilicity of a drug.

• Drugs that are verylipidsolubleor verywater-soluble i.e.,extremesin
partition coefficient,will demonstrate
 either lowfluxinto the tissues or
 rapid fluxfollowedbyaccumulation in tissues.
• Bothcasesare undesirable for controlled release system.
19

M O L E C U L A R S IZE
&
DIFFUSIVITY
20

MOLECULAR SIZE & DIFFUSIVITY
21
• In addition to diffusion through a variety of biological membranes, drugs
in many CRDDS must diffuse through a rate controlling membrane or
matrix.
• The ability of drug to pass through membranes, its so called diffusivity, is
a function of its molecular size (or molecular weight).
• Animportant influence upon the value of diffusivity, D, in polymers is the
molecularsize ofthe diffusingspecies.
• The value of D thus is related to the size and shape of the cavities as well
as sizeand shape ofthe drugs.

MOLECULAR SIZE & DIFFUSIVITY
• Molecular size of the drug plays a major role when it comes to
diffusion ofthe drug through a biologicalmembrane.
1. Massspectroscopy (MSor LC-MS)are generallyused as the most
common methods to determine the molecularsizeofthe drug.
2. FourierTransform IR-spectroscopy (FTIR)isalsoused to
determine the molecular structure.
• Diffusion ofthe drug from the matrix or encapsulated form determines
the release rate ofthe drug from the polymer.
• Diffusivityis the rate determining step inCRDDS. 23

DOSE SIZE
• Size of the drug plays a major role in determining the size of the final
finished product.
• In case, the dose already high, then formulating the same into controlled
release will further increase the overall dosage size & thereby reduced
patientcompliance.
• For drugs with an elimination half-life of less than 2 hours as well as those
administered in large doses, a controlled release dosage form may need to
carry a prohibitively large quantity of drug.
24

COMPLEXATION
• Complexation is one of the well known method to entrap the drug
within a complexingagent likeβ-cyclodextrincomplex.
• These complexes could be helpful in entrapping drugs of very high
molecularweight whichhavelowdiffusivitythrough the membrane.
• From formulation point of view, this property also facilitates in
increasing the solubilityofthe drug in the requiredsolvent.
26

IONIZATION CONSTANT
• This factor have important effects on a wide range of issues including,
Dissolution, Membrane partition, Complexation,Chemicalstability & drug
absorption.
• Fromthe site ofrelease ofthe drug, it’s absorption depends uponits
ionization constant.
• And, it has been depicted that drugs in unionized form are absorbed
faster than the ionized species.
28

IONIZATION CONSTANT
[B] =conc.ofthe ionizedbase
ionized &• The Henderson-Hasselbalch eq. provides an estimate of
unionized drug conc,byfunction of pH…………
Acidic drugs: pKa=- log10(Ka)=pH+log10([HA]/[A-])
Basic drugs : pKa=- log10(Kb)=pH+log10([HB+]/[B-])
• Where:
Ka or Kb =ionizationconstant for acid/basic drugs
[HA] =conc.ofunionized acid
[A-] =conc.ofionized acid
[HB+] =conc.ofthe unionizedbase
30

DRUG STABILITY
• Since most oral controlled release systems are designed to release their
contents overmuch ofthe length ofGI tract,
 drugs that are unstable in the environment ofthe intestine
 drugs that are unstable in the environment ofthe stomach
• might be difficultto formulate into prolonged release system.
• In order to counter-act such problems, several modified-release methods
have been adopted that restricts the release at the required site of the
GIT.
31

PROTEIN BINDING
33
• It refers to the formation of complex with the blood proteins (like
albumin) with the absorbed drug.
• Thiscomplexleadsto….
 Inhibition of therapeutic effect of suchamount
 Half-life is increased(compared to invitro studies)
 Toxicityprofiles elevated
• Thus,in most ofthe cases,protein binding is undesirable.
• Manydrugs are highlyprotein binding (maybe 95%),thus the need of
formulating a modifieddrug or drug deliverysystem starts.

FACT: 01
• Generally, the values of diffusion coefficient for intermediate molecular
weight drugs i.e., 150-400 Dalton, through flexible polymers range from
10-6to 10-9cm2/sec,with valueson the order of10-8being most common.
35

FACT: 2
• Fordrugs with molecularweightgreater than 500 Dalton,thediffusion
coefficients in many polymers frequently are so small that they are
difficult to quantify, i.e.,lessthan 10-12cm2/sec.
• Thus, high molecular weight of drug should be expected to display very
slow release kinetics in sustained release devices where diffusion through
polymericmembrane or matrix isthe release mechanism.
36

Approaches in Design Considerations
 Chemical approach
 Biological approach
 Pharmaceutical approach
37

PHARMACEUTICAL Approaches
Controlled
(Combination)
A. Dissolution controlled Release C. Dissolution-Diffusion
 Encapsulationdissolutioncontrol
 Matrixdissolutioncontrol
B.DiffusionControlledRelease
 Membrane material
 Solution-diffusion membrane
 Rateofpermeation
• Drug diffusion coefficientin the
polymer
• Polymer/solution partition
coefficient
38

PHARMACEUTICAL Approaches
A.DissolutioncontrolledRelease
 Encapsulationdissolutioncontrol
 Matrixdissolutioncontrol
B.DiffusionControlledRelease
 Reservoir devices
 Matrix devices
39

INTRODUCTION
• Control – Dissolution of the drug from the polymer matrix
or encapsulated forms.
• The dissolution process at a steady state is described
by NoyesWhitneyequation:
dc/ dt=kA/V(Cs–C)
dc/ dt=(D/h)A(Cs– C)
where, dC/dt
V
k
D
h
A
Cs
C
=dissolution rate
=volumeofthesolution
=dissolution rate constant
=diffusion coefficientofdrug through pores
=thickness ofthe diffusionlayer
=surface area ofthe exposed solid
=saturated solubility ofthedrug
=conc.ofdrug in the bulksolution 42

TYPES
• Offollowingtypes based on TECHNICALSOPHISTICATION:
1. Matrix type
2. Encapsulation type
42

MATRIX type
(Dissolution-Controlled)
43

MATRIX type
• Matrixdissolution devicesare prepared bycompressing the drug with slowly
dissolving carrier into tablet
• Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolvingat slower rate.
Drug
Reservoir
Rate-
Controllingsurfac
e
Dru
g
44

MATRIX type
• First order drug release.
• There are 2 methods:
1.Congealing &
2. Aqueousdispersionmethod
• Thedrug release is determined bydissolution rate ofthepolymer.
• Examples:
1. Dimetane extencaps,
2. Dimetapp extentabs.
45

ENCAPSULATEDtype
(Dissolution-Controlled)
46

ENCAPSULATION type
• The drug particle are coated or encapsulated by microencapsulation
are filled in hard gelatin capsule, popularly called as
technique
• The pellets
‘spansules’.
• Once the coating material dissolves the entire drug inside the
microcapsule isimmediatelyavailablefor dissolution and absorption.
• Herethe drug release isdetermined bydissolution rate and thicknessof
polymer membrane whichmayrange from 1to 200µ
47

ENCAPSULATION type
• Calledas Coatingdissolution controlledsystem.
• Dissolutionrate ofcoat depends upon stability&thicknessof coating.
• One ofthe microencapsulation method isused.
• Examples:
1.Ornade spansules,
2. Chlortrimeton Repetabs
48

ENCAPSULATION type
Soluble drug
Slowly
dissolving
or erodible
coat
49

INTRODUCTION
• Thissystem ishollowcontaining an inner core of drug.
• Thewater insolublepolymericmaterial surrounds drug reservoir.
• Thedrug partitions into the membrane and exchangeswith the surrounding
fluidbydiffusion.
• The release drug from a reservoir device follows Fick’sfirst law of diffusion.
J=- Ddc/dx
Where, J =flux, amount/area-time
D =diffusioncoefficientofdrug in the polymer, area/time
dc/dx =changein conc.with respect to polymer distance
52

TYPES
• Offollowingtypes based on TECHNICALSOPHISTICATION:
1. Reservoir Devices
2. Matrix Devices
52

RESERVOIR Devices
(Diffusion-Controlled)
53

Reservoir device
RESERVOIR DEVICES
54
a) Spherical type
b) Slab type
Rate controlling
steps :
• Polymeric content in
coating,
• Thickness of coating,
• Hardness of
microcapsule.

RESERVOIR Devices
55
• Thedrug core isencased bya water-insolublepolymeric materials.
• The mesh (i.e., the space between macromolecular chains) of these polymers,
through which drug penetrates or diffuses after partitioning, is of MOLECULAR
LEVEL.
• The rate of drug release is dependent on the rate of drug diffusion but not on
the rate of dissolution.
• Inshort, masstransportphenomena at molecular leveloccurs.
• Examples:Nico-400, Nitro-Bid

Methods of Prep. (RESERVOIR Devices)
• Mostlyit involves :
o Coated Beads/Pellets
o Microencapsulation
56

Coated Beads/Pellets (RESERVOIR Devices)
• BEADS/PELLETS
Coatingofdrug solution onto preformed cores.
Coveringofcore byan insoluble(but permeablecoat).
NOTE: Pan coating or air-suspension technique is generally used for
coating.
NOTE:Poreforming additivesmaybe added to the coatingsolution.
57

Microencapsulation (RESERVOIR Devices)
• Thistechnique used to encapsulatesmallparticles ofdrug, solutionof
drug, or even gases in a coat (usually a polymer coat).
• Generally, any method that can induce a polymerbarrierto deposit on the
surface of a liquid droplet or a solid surface can be used to form
microcapsules.
58

Microencapsulation (RESERVOIR Devices)
• Techniques:
1. Coacervation (Polymers: gelatin,acacia, PA, EC, etc.)
2. Interfacial polymerization (Polymers: polyurethanes,
polyamides,polysulfonamides,polyphtalamides,etc.)
3. Solvent evaporation
4. Others (thermal denaturation, hot melt, spray-drying,
60
salting out,etc.)

MATRIX Devices
(Diffusion-Controlled)
60

MATRIX Devices
• Amatrix or monolithic deviceconsists ofan inert polymericmatrix in
whicha drug isuniformly distributed.
• Drugs can be dissolvedin the matrix or the drugs can be present as a
dispersion.
NOTE : Matrix may be HOMOGENEOUS or POROUS with water filled
pores.
62

MATRIX Devices
• State ofpresentation ofthis form affects the variousrelease patterns:
1. Dissolveddrug (Fick’sSecondlaw)
2. Dispersed drug (Fick’sFirstlaw)
3. Porous matrix (Higuchi’stheory for porous form)
4. Hydrophilicmatrix (gelation&diffusion)
63

MATRIX Devices
• RigidMatrixDiffusion
 Materials used are insoluble plastics such asPVP&fattyacids.
• SwellableMatrixDiffusion
1. Also called as Glassy hydrogels.Popular for sustaining the release of
highlywater soluble drugs.
2.Materials used are hydrophilicgums.
Examples:Natural- Guar gum, Tragacanth.
Semisynthetic -HPMC,CMC,Xanthumgum.
Synthetic -Polyacrilamides.
• Examples:GlucotrolXL,Procardia XL 65

RECENTTrends
(Marketed Products)
66

Recent Trends
• Products inmarket:
 Cordicant -uno®
 Madopar DR
 SULARER
• This technology controls amount, timing and
locationofrelease in body.
• Formulation with predictable and reproducible
drug releaseprofile.
• Controls rate of drug diffusion throughout
release process,ensuring 100%release Products 67
Recent trend

Ndds 1 classification of crdds part 3

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