Various methods to enhance dissolution rate and bioavailability

1. Methods to enhance the
dissolution rates and bioavailability of
poorly soluble drugs
R. Nagaraju M.Pharm.,Ph.D
Professor Pharmaceutics
Institute of Pharmaceutical Technology
Sri Padmavathi Mahila Visvavidyalayam
Tirupati

2. Status of Modern APIs:
About 95% of all new potential therapeutics have poor
pharmacokinetic and biopharmaceutical properties. (Ref. Brayden DJ,
Controlled release technologies for drug delivery, Drug Discov.Today, 2003, 8, 976-8.)
 Lipophilic
 poor aqueous solubility
 belong to class II under BCS (LS,HP)
 exhibit low and variable bioavailability
 Needs enhancement in bioavailability to derive the maximum
therapeutic efficacy.

3. BIOPHARMACEUTICAL
CLASSIFICATION SYSTEM (BCS)

4. Class I
Propranolol, Metoprolol,
Diltiazem, Verapamil
Class III
Acyclovir, Neomycin B,
Captopril, Enalaprilate,
Alendronate
Class II
Ketoconazole, Mefanamic
acid, Nisoldipine,
Nifedipine, Nicardipine,
Felodipine
Class IV
Chlorothiazide,
Furosimide,
Tobramycin,
Cefuroxime
HIGH LOW
BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)
Solubility
Permeability

5. BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)
Class Characteristics
I HS/HP
• Conventional products like an oral solution
• Dissolution and absorption is very rapid
• BA / BE studies are unnecessary
• Highly suitable for CR / SR
• CR by controlling release rate
II LS/HP
 Solubility / Dissolution rate is rate controlling step
 Variable bioavailability
 Needs enhancement in dissolution rate for increasing BA
 Suitable for CR / SR
III HS/LP
 Permeation is rate controlling step
 BA is independent of drug release from the dosage form
 Low BA
Needs enhancement of permeability (permeation enhancers)
 Problematic for CR / SR
IV LS/LP  Poor and variable BA
 Unsuitable for CR / SR

6. BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)
RATE LIMITING PROCESS IN THE ABSORPTION
Class I Gastric emptying (Conventional)
Release rate (Controlled Release)
Class II Dissolution (or) Release
Class III Permeability
Class IV Various Factors

7. METHODS FOR ENHANCING
THE DISSOLUTION RATE
1. Methods that increase the solubility of the drug:
 Buffering the pH of the diffusion layer (e.g., Buffered
aspirin tablets)
 Use of salts of weak acids and weak bases (e.g., Sodium
and Potassium salts of penicillin)
 Use of solvates and hydrates (e.g., Ampicillin anhydrate)

8. • Use of selected polymorphic form (e.g., Novobiocin,
Chloramphenicol palmitate)
• Complexation (e.g., Digoxin Hydroqunone,
cyclodextrin complexes)
• Pro-drug approach (e.g., 21-disodium phosphate
ester of methasone)
• Use of surfactants

9. METHODS FOR ENHANCING THE DISSOLUTION RATE
2. Methods that increase the surface area of the drug:
 Micronization
 Use of surfactants
 Solid dispersion in highly soluble carriers
 Solvent deposition on inert materials

10. COMMONLY USED INTESTINALABSORPTION ENHANCERS
Bile salts Sodium cholate, sodium deoxycholate
Nonionic surfactants
Polysorbates and polyoxyethylene alkyl esters
and ethers
Ionic surfactants Sodium lauryl sulphate and dioctyl
sulfosuccinate
Fatty acids Sodium caprate, oleic acid
Glycerides Medium-chain glycerides, phospholipids
Acyl carnitines Palmitoylcarnitine
Chelating agents EDTA
Swellable polymers Polycarbophil and chitosan

11. Drug Delivery Technologies for
Insoluble Drugs
Use of Salts, Solvates, Hydrates, Polymorphic
forms, Surfactants, Complexation, Prodrugs,
Micronization, Solid dispersions and Solvent
deposited systems, etc.
Conventional Techniques:

12. CYCLODEXTRIN BASED DRUG
DELIVERY

13. Cyclic (- 1, 4) linked oligosaccharides of
 - D – gluco- pyranose units
O
OH
HOH 2C
HO
O
O
O
CH2OH
HO
HO
O
CH2OH
HO
HO
O
O
O
O
O
OH
CH2OH
HO
O
OH
OHO
CH2OH
O
HOH 2C OH
OH
HOH 2C
OH
OH
CD HP-CD
Structure of Cyclodextrins
CYCLODEXTRINS

14. CYCLODEXTRINS
 Contain a relatively hydrophobic central cavity and
hydrophilic outer surface
 Torus or Cone shaped
 Form inclusion complexes
 Parent cyclodextrins are -, - and - cyclodextrins,
which consist of six, seven and eight glucopyranose units,
respectively
O
OH
HOH 2C
HO
O
O
O
CH2OH
HO
HO
O
CH2OH
HO
HO
O
O
O
O
O
OH
CH2OH
HO
O
OH
OHO
CH2OH
O
HOH 2C OH
OH
HOH 2C
OH
OH

15. CYCLODEXTRIN COMPLEXATION
 A rapidly reversible process
A 1 in 100 dilution, needed for complete release of drug
from the CD complex
 To improve pharmaceutical properties like
solubility
dissolution rate
bioavailability
stability and
palatability
without affecting their intrinsic lipophilicity or
pharmacological properties

16.  PGE1 - CD an intra-arterial infusion (Prostandin of M/s
Ono, Japan and Prostavasin of M/s Schwarz Pharma,
Germany & Italy).
 Ziprasidone – SBE-CD – an intramuscular injection
(Zeldox of M/s. Pfizer, Sweden & USA).
 Itraconazole – HP-CD – oral and i.v. solutions (Sporanox
of M/s. Janssen, USA and Belgium).
 Piroxicam-CD-oral liquids in several countries under
various trade names.
COMMERCIAL CD BASED FORMULATIONS

17. Size Reduction Technologies
Bottom up Technologies (Precipitation methods)
Top Down Technologies (Disintegration methods)
 Media milling : High shear media milling
(Elan Pharmaceuticals)
Milling media – Polystyrene resin, Water, Drug
Stabilizers – Pluronics, polysorbates, povidones.

18.  Homogenization in water : Dissocubes of Skye Pharma &
Stabilizers, Surfactants Nanoedge Technology of Baxter
and Polymers
 Homogenization in
Non-aqueous Media : Nanopure of PharmaSol, Berlin
Water miscible PEGs
Size Reduction Technologies
Top Down Technologies (Disintegration methods)

19. Precipitation Technologies
EPAS: Evaporative Precipitation into Aqueous
Solution
Controlled Precipitation

20. CONCLUSION
Developing drug delivery technologies for
insoluble drugs is a promising area for
continued research with the aim of improving
their bioavailability and therapeutic
effectiveness.

21. THANK YOU