This document discusses factors affecting the design of controlled release drug delivery systems (CRDDS). It outlines several key considerations for CRDDS design including selection of the drug candidate, medical and biological rationale, and physicochemical properties. It also discusses important physicochemical factors such as solubility, partition coefficient, molecular size and diffusivity, dose size, complexation, ionization constant, drug stability, and protein binding that influence CRDDS design. Finally, it briefly describes dissolution-controlled and diffusion-controlled release approaches for developing CRDDS.

1. 01
CONTROLLED RELEASE
DDS
Project date 20/09/2013
Al Ameen College of
Pharmacy
BY:
SURAJ CHOUDHARY
M.PHARM (PHARMACEUTICS)
DEPT. OF PHARMACEUTICS
Factors & Types

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

3. RECAP
3
THEME QUESTION -1
THEME QUESTION -2
FLASHBACK
COMPARISON - 1
COMPARISON - 2
MOVEMENT RESTRICTIONS
CRDDS DESIGN CONSIDERATIONS
PRE-REQUISITES
CLASSIFICATION
CONCEPT-BASED ON CLASSES
RECENT INNOVATIONS

4. FACTORS
AFFECTING THE DESING OF CRDDS
4

5. FACTORS Consideration
for
CRDDS Design
o Selection of drug candidate
o Medical Rationale
o Biological Factors
o Physico-Chemical Properties
o In vitro analysis
o Formulation optimization
o In vivo data generation
o Discussion with Regulatory Authorities
o Data submission to Regulatory Authorities
for Marketing, Authorization / Approval.
5

6. SELECTION OF Drug Candidate
 Very short or very long half-life X
 Significant first pass metabolism X
 Poor absorption throughout the GI tract X
 Low solubility X
 Large no. of dose X
 Narrow therapeutic window X
6

7. MEDICAL Rationale
 Frequency of Dosing
 Patient compliance
 Drug intake
 Fluctuation of serum concentration
 Reduced side effect
 Sustained efficacy
7

8. BIOLOGICAL Rationale
 Absorption
 Distribution
 Elimination
 Dose Dependent Bio-Availability
 Drug -Protein Binding
 Duration of Action (Half – life)
 Margin of Safety
 Disease Condition
8

9. PHARMACO-KINETIC/DYNAMIC
Considerations
 Dose Dumping
 First Pass metabolism
 Enzyme Induction/Inhibition upon multiple dosing
 Variability of urinary pH effect on drug elimination
 Prolonged drug absorption
 Variability in GI Empting and motility
9

10. PHYSICO-CHEMICAL Considerations
 Solubility & pKa
 Partition Coefficient
 Molecular Size &
Diffusivity
 Dose size
10
 Complexation
 Ionization Constant
 Drug stability
 Protein Binding

11. 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
device approaches 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

12. PHYSICO-CHEMICAL
FACTORS
AFFECTING THE DESING OF CRDDS
12

13. SOLUBILITY
&
pKa
13

14. SOLUBILITY & pKa
• The solubility of a solid substance is defined as…….
“ the concentration at which the solution phase is in equilibrium
with a given solid phase at a stated temperature & pressure.”
• To improve solubility:
Solvation Complexation
Hydration Recrystallization
Co-solvation Use of surface active agents
• NOTE: A classification is given as per the permeability & solubility
profile, known as BCS Classification.
14

15. SOLUBILITY & pKa
• Determination of solubility:
1. Semi-quantitative method
2. Accurate-quantitative method
3. pH-change method
15

16. 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.
16

17. PARTITION
COEFFICIENT
17

18. PARTITION COEFFICIENT
• The partition coefficient is defined as…….
“ the concentration ratio of unionized drug distributed between
two phases at equilibrium.”
• Given by the Noyes-Whitney’s Equation:
P = [퐴]표/([퐴]∞)
• The logarithm (base 10) of the partition coefficient (log10P) is often
used.
18

19. PARTITION COEFFICIENT
• For ionizable drugs, where the ionized species does not partition into
the organic phase, the APPARENT partition 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.
19

20. PARTITION COEFFICIENT
• Drugs that are very lipid soluble or very water-soluble i.e., extremes in
partition coefficient, will demonstrate
 either low flux into the tissues or
 rapid flux followed by accumulation in tissues.
• Both cases are undesirable for controlled release system.
20

21. MOLECULAR SIZE
&
DIFFUSIVITY
21

22. MOL. SIZE & DIFFUSIVITY
• 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).
• An important influence upon the value of diffusivity, D, in polymers is
the molecular size of the diffusing species.
• The value of D thus is related to the size and shape of the cavities as
well as size and shape of the drugs.
22

23. MOL. SIZE & DIFFUSIVITY
• Molecular size of the drug plays a major role when it comes to
diffusion of the drug through a biological membrane.
1. Mass spectroscopy (MS or LC-MS) are generally used as the
most common methods to determine the molecular size of the
drug.
2. Fourier Transform IR- spectroscopy (FTIR) is also used to
determine the molecular structure.
• Diffusion of the drug from the matrix or encapsulated form determines
the release rate of the drug from the polymer.
• Diffusivity is the rate determining step in CRDDS. 23

24. DOSE
SIZE
24

25. 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 patient compliance.
• 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.
25

26. COMPLEX
FORMATION
26

27. COMPLEXATION
• Complexation is one of the well known method to entrap the drug
within a complexing agent like β-cyclodextrin complex.
• These complexes could be helpful in entrapping drugs of very high
molecular weight which have low diffusivity through the membrane.
• From formulation point of view, this property also facilitates in
increasing the solubility of the drug in the required solvent.
27

28. IONIZATION
CONSTANT
28

29. IONIZATION CONSTANT
• This factor have important effects on a wide range of issues including,
Dissolution, Membrane partition, Complexation, Chemical stability &
drug absorption.
• From the site of release of the drug, it’s absorption depends upon its
ionization constant.
• And, it has been depicted that drugs in unionized form are absorbed
faster than the ionized species.
29

30. IONIZATION CONSTANT
• The Henderson-Hasselbalch eq. provides an estimate of ionized &
unionized drug conc, by function of pH…………
Acidic drugs: pKa = - log10(Ka) = pH + log10([HA]/[A-])
Basic drugs : pKa = - log10(Kb) = pH + log10([HB+]/[B-])
• Where:
Ka or Kb = ionization constant for acid/basic drugs
[HA] = conc. of unionized acid
[A-] = conc. of ionized acid
[HB+] = conc. of the unionized base
[B] = conc. of the ionized base
30

31. STABILITY
OF DRUG
31

32. DRUG STABILITY
• Since most oral controlled release systems are designed to release their
contents over much of the length of GI tract,
 drugs that are unstable in the environment of the intestine
 drugs that are unstable in the environment of the stomach
• might be difficult to 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.
32

33. PROTEIN
BINDING
33

34. PROTEIN BINDING
• It refers to the formation of complex with the blood proteins (like
albumin) with the absorbed drug.
• This complex leads to….
 Inhibition of therapeutic effect of such amount
 Half-life is increased (compared to invitro studies)
 Toxicity profiles elevated
• Thus, in most of the cases, protein binding is undesirable.
• Many drugs are highly protein binding (may be 95%), thus the need of
formulating a modified drug or drug delivery system starts.
34

35. NOTE- 1 & 2
35

36. NOTE – 1
• Generally, the values of diffusion coefficient for intermediate molecular
weight drugs i.e., 150-400 Dalton, through flexible polymers range from
10-6 to 10-9 cm2/sec, with values on the order of 10-8 being most
common.
36

37. NOTE – 2
• For drugs with molecular weight greater than 500 Dalton, the diffusion
coefficients in many polymers frequently are so small that they are
difficult to quantify, i.e., less than 10-12 cm2/sec.
• Thus, high molecular weight of drug should be expected to display very
slow release kinetics in sustained release devices where diffusion
through polymeric membrane or matrix is the release mechanism.
37

38. Approaches in Design Considerations
 Chemical approach
 Biological approach
 Pharmaceutical approach
38

39. PHARMACEUTICAL Approaches
C. Dissolution-Diffusion Controlled
(Combination)
A. Dissolution controlled Release
 Encapsulation dissolution control
 Matrix dissolution control
B. Diffusion Controlled Release
 Membrane material
 Solution-diffusion membrane
 Rate of permeation
• Drug diffusion coefficient in the
polymer
• Polymer/solution partition
coefficient
39

40. PHARMACEUTICAL Approaches
A. Dissolution controlled Release
 Encapsulation dissolution control
 Matrix dissolution control
B. Diffusion Controlled Release
 Reservoir devices
 Matrix devices
40

41. DISSOLUTION CONTROLLED

42. INTRODUCTION
• Control – Dissolution of the drug from the polymer matrix
or encapsulated forms.
• The dissolution process at a steady state is described by
Noyes Whitney equation:
dc / dt = k A/V (Cs – C)
dc / dt = (D/h) A (Cs – C)
where, dC/dt = dissolution rate
V = volume of the solution
k = dissolution rate constant
D = diffusion coefficient of drug through pores
h = thickness of the diffusion layer
A = surface area of the exposed solid
Cs = saturated solubility of the drug
C = conc. of drug in the bulk solution 42

43. TYPES
• Of following types based on TECHNICAL SOPHISTICATION:
1. Matrix type
2. Encapsulation type
43

44. MATRIX type
(Dissolution-Controlled)
44

45. MATRIX type
• Matrix dissolution devices are prepared by compressing the drug with slowly
dissolving carrier into tablet
• Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolving at slower rate.
Drug Reservoir
Rate-Controlling
surface
Drug
45

46. MATRIX type
• First order drug release.
• There are 2 methods:
1. Congealing &
2. Aqueous dispersion method
• The drug release is determined by dissolution rate of the polymer.
• Examples:
1. Dimetane extencaps,
2. Dimetapp extentabs.
46

47. ENCAPSULATED type
(Dissolution-Controlled)
47

48. ENCAPSULATION type
• The drug particle are coated or encapsulated by microencapsulation
technique
• The pellets are filled in hard gelatin capsule, popularly called as
‘spansules’.
• Once the coating material dissolves the entire drug inside the
microcapsule is immediately available for dissolution and absorption.
• Here the drug release is determined by dissolution rate and thickness of
polymer membrane which may range from 1 to 200μ
48

49. ENCAPSULATION type
• Called as Coating dissolution controlled system.
• Dissolution rate of coat depends upon stability & thickness of coating.
• One of the microencapsulation method is used.
• Examples:
1. Ornade spansules,
2. Chlortrimeton Repetabs
49

50. ENCAPSULATION type
50
Soluble drug
Slowly
dissolving
or erodible
coat

51. DIFFUSION CONTROLLED

52. INTRODUCTION
• This system is hollow containing an inner core of drug.
• The water insoluble polymeric material surrounds drug reservoir.
• The drug partitions into the membrane and exchanges with the surrounding
fluid by diffusion.
• The release drug from a reservoir device follows Fick’s first law of diffusion.
J = - D dc/dx
Where, J = flux, amount/area-time
D = diffusion coefficient of drug in the polymer, area/time
dc/dx = change in conc. with respect to polymer distance
52

53. TYPES
• Of following types based on TECHNICAL SOPHISTICATION:
1. Reservoir Devices
2. Matrix Devices
53

54. RESERVOIR Devices
(Diffusion-Controlled)
54

55. Reservoir device
RESERVOIR DEVICES
a) Spherical type
b) Slab type
55
Rate controlling
steps :
• Polymeric content in
coating,
• Thickness of coating,
• Hardness of
microcapsule.

56. RESERVOIR Devices
• The drug core is encased by a water-insoluble polymeric 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.
• In short, mass transport phenomena at molecular level occurs.
• Examples: Nico-400, Nitro-Bid
56

57. Methods of Prep. (RESERVOIR Devices)
• Mostly it involves :
o Coated Beads/Pellets
o Microencapsulation
57

58. Coated Beads/Pellets (RESERVOIR Devices)
• BEADS/PELLETS
Coating of drug solution onto preformed cores.
Covering of core by an insoluble (but permeable coat).
NOTE: Pan coating or air-suspension technique is generally used for
coating.
NOTE: Pore forming additives may be added to the coating solution.
58

59. Microencapsulation (RESERVOIR Devices)
• This technique used to encapsulate small particles of drug, solution of
drug, or even gases in a coat (usually a polymer coat).
• Generally, any method that can induce a polymer barrier to deposit on
the surface of a liquid droplet or a solid surface can be used to form
microcapsules.
59

60. 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,
salting out, etc.)
60

61. MATRIX Devices
(Diffusion-Controlled)
61

62. DRUG DELmIVaERtrYi xFR dOeMv TicYPeICsAL
MATRIX DEVICES
62

63. MATRIX Devices
• A matrix or monolithic device consists of an inert polymeric matrix in
which a drug is uniformly distributed.
• Drugs can be dissolved in the matrix or the drugs can be present as a
dispersion.
NOTE : Matrix may be HOMOGENEOUS or POROUS with water filled
pores.
63

64. MATRIX Devices
• State of presentation of this form affects the various release patterns:
1. Dissolved drug (Fick’s Second law)
2. Dispersed drug (Fick’s First law)
3. Porous matrix (Higuchi’s theory for porous form)
4. Hydrophilic matrix (gelation & diffusion)
64

65. MATRIX Devices
• Rigid Matrix Diffusion
 Materials used are insoluble plastics such as PVP & fatty acids.
• Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for sustaining the release of
highly water soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum, Tragacanth.
Semisynthetic -HPMC, CMC, Xanthum gum.
Synthetic -Polyacrilamides.
• Examples: Glucotrol XL, Procardia XL 65

66. RECENT Trends
(Marketed Products)
66

67. Recent Trends
• Products in market:
 Cordicant -uno®
 Madopar DR
 SULAR ER
• This technology controls amount, timing and
location of release in body.
• Formulation with predictable and reproducible
drug release profile.
• Controls rate of drug diffusion throughout
Recent trends: release process, ensuring 100% release Products 67

68. references
1. Chien Y W; Novel Drug Delivery Systems; Informa Healthcare, 2nd
68
Edition, 2009.
2. Siegel R A and Rathbone M J; Overview of Controlled Release
Mechanisms; Advances in Delivery Science and Technology, 2012.
3. Bhowmik D, et.al; Recent trends in scope and opportunities of control
release oral drug delivery systems; Critical review in pharmaceutical
sciences, (1): 2012.
4. Ummadi S, Shravani B; Overview on Controlled Release Dosage Form;
International Journal of Pharma Sciences, 3(4); 2013.

69. 03
THANK YOU.
69
For Attention!!!!