The document discusses methods for enhancing the solubility of poorly soluble drugs, focusing on pH alteration and complexation techniques. It explains how solubility can be influenced by pH for both weak acids and bases and details the use of cyclodextrins in improving drug delivery and stability. Additionally, it outlines various characterization methods for inclusion complexes and highlights the advantages of cyclodextrins over organic solvents in pharmaceutical applications.

1. SEMINAR ON SOLUBILITY ENHANCEMENT BY 1. ALTERATION IN pH OF THE SOLVENT SYSTEM 2. COMLEXATION TECHNIQUES

2. CONTENTS: Solubilization by pH Handersson-Hasselbach equation Solubilization by complexation Self association and stacking complexation Inclusion complex Solubilization using combination of pH and complexation References /39

3. SOLUBILIZATION It is defined as the process of enhancement of solubility of a very slightly soluble or a insoluble drug to dissolve in a suitable solvent for desired formulation. /39

4. SOLUBILIZATION BY pH Drug should be dissolve in an aqueous media. The ionized form of the drug has responsible for solubility of drug. For weak acidic drugs, Lower pH Unionized form insoluble/ ppt. Higher pH ionized form more soluble drug. For weak basic drugs, Lower pH ionized form more soluble drug. Higher pH Unionized form insoluble/ ppt. /39

5. Dissociation constant for Acidic/Basic drug expressed by pKa values. /39 Lower pKa Stronger the Acid More ionization Higher pKa Stronger the Base More ionization

6. Handersson-Hasselbach Equations For weak Acid, pH=pK a +log For weak Base, pH=pK a +log /39

7. This equation helps to find out, 1) Solubility of a drug at particular pH. 2)Minimum pH range that must be maintain to prevent precipitation of the drug /39

8. Weak acids: e.g. Nimesulide; 51 fold increase in solubility by shifting pH from 1.2 to 8.4 Other examples: Aspirin, Phenytoin, Penicillin, Cephalosporin, etc. /39 Drugs showing enhancement in solubility up on alteration in pH. pH Solubility mg/ml 1.2 0.70 6.2 0.86 7.4 4.10 8.4 43.90

9. Weak bases: Similar increase in solubility of Levemopamil HCl by decreasing pH. Other examples; Morphine, Ephedrine, Itraconazole, Flavopiridol, etc. /39

10. Zwitter ion compounds: Pelrinone HCL; pH 3-5 Cationic form pH 5-8 Neutral form pH 8-11 Anionic form Other examples; Loraxepam, Proteins, Amino acids, etc. /39

11. Divalent compounds: The solubilization of divalent acids/bases is similar to that of monoprotic compound. However due to ionization of second acid group solubility increases up to 100 fold for change in 1 pH unit. /39

12. Solubilization by Complexation /39

13. The mathematical description for the equilibrium constant of a 1:1 complex K 1:1 = [SL] / [S] [L] K 1:1 is defined as equilibrium constant/ Stability constant/ Complexation constant. /39

14. Self association and Stacking Complexation /39 Complexes stacked can be homogeneous or mixed.

15. Examples of substances that interact in an aqueous media by stacking are, Naphthalene, Benzoic acid, Pyrene, Methylene blue, Caffeine etc. /39

16. Inclusion Complexes* Inclusion of a nonpolar molecule or the nonpolar region of a molecule (guest) into the nonpolar cavity of another molecule or group of molecules ( host). When the guest molecule enters the host molecule the contact between water and the nonpolar regions of both is reduced. * Ref: Current perspectives of solubilization potential for improved bioavailability (C.A; 147 (16) 350123x: OCT; 2007) /39

17. Cyclodextrins These cyclic oligomers of glucose are relatively soluble in water and have cavities large enough to accept common nonpolar portion of the drugs. Naturally occurring cyclodextrines obtained from action of Bacillus marcerans amylase on starch to form homogenous cyclic α ,(1->4) linkage glycoprotein. 6, 7, 8 glucopyranose units are termed α, β , γ , respectively. /39

18. The Natural Cyclodextrins α-Cyclodextrin Of somewhat limited value due to low complexation efficiency with most drugs. β-Cyclodextrin* This cyclodextrin does usually possess rather good complexation efficiency with drugs. However, β-cyclodextrin, and its complexes have very limited aqueous solubility. *Ref: Process for the preparation of formulation of angiotension converting enzyme inhibitor and product. (C.A: 147(11) 243338z; SEP;2007) /39

19. γ -Cyclodextrin Favorable toxicological profile. However, γ -cyclodextrin has frequently lower complexation efficiency than β-cyclodextrin. /39

20. Characteristics of CDs The conventional thoughts: CDs are not perfectly cylindrical, owing to lack of rotation about the bonds connecting the glucopyranose units But are truncated cone shaped. /39 β-Cyclodextrin: Seven α -1,4-linked gluco- pyranose units form a cone with a hydrophilic outer surface and a lipophilic cavity in the center.

21. Cyclodextrin Derivatives of Pharmaceutical Interest /39 RM β CD( Randomly methylated β -CD) HP β CD( Hydroxy propyl β -CD)* HP γ CD(Hydroxy propyl γ -CD) DM β CD( 2,4- dimethyl β -CD)** SBE β CD( Sulfobutylether β -CD)

22. *Ref: Complexation of ketoprofen with Hydroxypropyl β -CD. The inclusion complex 0f KPF- 2 HP β -CD could be formed spontaneously and lower temp is benefit to the formation. Hence, the solubility of KPF in aqueous solution increase. **Ref: Novel approach for pharmaceutical application of cyclodextrins. Among the natural CDs, bioadaptable γ -CD is particularly in the addition, the multifunctional characteristic of DM β -CD allow alleviation of undesirable properties of drug molecules through the formation of inclusion complexes. /39

23. Complex formation /39 From Frömming and Szejtli: Cyclodextrins in Pharmacy Kluwer Acad. Press, Dordrecht, 1994 .

24. Release of drug molecule from the complex Complexation of drugs by CDs does not interfere with their activity because complexation is a rapidly reversible process. After administration, the drug is release from complex upon dilution. Competitive displacement. /39

25. Solubilization using combination of pH and Complexation* The effect of pH on solubilization by complexation depends entirely on the solute and the ligand. If the ligand or the solute ionize with pH, the stability constant typically decreases. However , even with a decrease in the stability constant, author found that the combination of ionization and complexation can be a powerful method for solubilization. /39

26. There is significantly increase the solubility of a THIAZOLOBENZIMIDAZOLE derivative Combination of pH and complexation via HP β -CD. * Combined effect of HP β -CD and media pH on the solubility of PROSTGLANDIN E 1. Ref: C.A:147(13) 284709q; SEP; 2007 /39

27. Method for preparation of Cyclodextrin complex: Grinding Solid dispersion Neutralization method Kneading* Co-Precipitation Spray drying* Freeze drying Melting /39

28. * Chlorthalidone is a practically insoluble in water. HP β -CD used as a host molecule to improve it’s solubility in water via inclusion complex formation with the different ratio (1:1, 1:2). To form the CD and chlorthalidone complex KNEADING, SPRAY DRYING methods are used. *Ref: C.A:147(13) 284708p; SEP; 2007 /39

29. Characterization of Inclusion Complexes /39 Characterization in solid state: 1) Differential scanning calorimetry (DSC) 2) X-ray Powder diffraction (XRPD) 3) Fourier transform IR (FTIR) 4) Scanning electron microscopy (SEM) 5) Thermogravimetry (TG) Characterization in solution state: 1) Solubility study 2) TLC 3) NMR 4) UV studies

30. What are cyclodextrins used for? To increase aqueous solubility of drugs. To increase chemical stability of drugs. To enhance drug delivery to and through biological membranes. To increase physical stability of drugs. To convert liquid drugs to microcrystalline powders. To prevent drug-drug and drug-excipient interactions. To reduce local irritation after topical or oral administration. /39

31. Why are cyclodextrins better than organic solvents? Frequently less irritating after iv and im injection. Frequently less toxic. The drug does not precipitate after iv injection. * Example: Water soluble PROGESTERONE HP β -CD complex for injectable formulations. * Ref: C.A:147(17) 37141t; OCT; 2007 Can be used in solid dosage forms. /39

32. Parenteral solution containing diazepam 5 mg/ml Valium: Diazepam 5.0 mg Benzylalcohol 15.7 mg Ethanol 85.3 mg Propylene glycol 414.0 mg Benzoic acid 47.5 mg Purified water ad 1.00 ml About 45% water. /39 CD formulation: Diazepam 5.0 mg HP  CD 60.0 mg Sodium chloride 6.0 mg Purified water ad 1.00 ml About 93% water.

33. Advantage of  -Cyclodextrin: Liquid component can be transformed into a crystalline form Volatile component can be stabilized against losses through evaporation Molecules can be protect against oxidation. It can be used for taste and smell masking. Incompatible drug can be mixed together if one of them is protected by formation of Cyclodextrin complex. Solubility in water as well as the rate of dissolution of poorly soluble drug can be increased. /39

34. Application of  -cyclodextrin: /39

35. Some cyclodextrin-containing products World-wide there are close to 30 cyclodextrin containing pharmaceutical products on the market and most of them are marketed in more than one country. Almost half of them contain the natural  CD. /39

36. NEWER APPROACH TO SOLUBILIZATION Hydrophilic Solubilization Technology (HST) Lipophilic Solubilization Technology (LST) Zydis - Fast dissolve Technology Qdis – A Fast dissolve dosage form Supercritical Fluids in Solubilization /39

37. REFERENCES Encyclopedia of Pharmaceutical technology, Volume 3, Edited By James Swarbrick, 2458-2477 Encyclopedia of Pharmaceutical technology, Volume 18, Edited By James Swarbrick, 172-207 Physical Pharmacy, Third edition, By Alfred Martin The theory and practice of Industrial Pharmacy, By Leon Lachman The Science and Pharmacy practice Remington vol:1 Journal of Pharmaceutical Science, vol. 96, No. 7, July 2007 Indian Journal of Pharmaceutical Science, May-June, 2006, 301-307 Drug development and Industrial pharmacy.2007,39(8), 856-873 www.SCOLR.com /39