1. Solubility and Dissolution Pharmaceutical Technology

2. Solubility and Dissolution Solubilization of poorly soluble drugs is a frequently encountered challenge in screening studies of new chemical entities as well as in formulation design and development. This is simply due to bioavailability considerations. Bioavailability is defined as the rate and extent to which the active drug is absorbed from a dosage form and becomes available at the site of drug action

3. Solubility and Dissolution Oral administration is obviously the most preferable dosage route. The oral absorption of a drug is the tandem process of the dissolution and the intestinal membrane permeation of a drug in the gastrointestinal (GI) tract. However, only solubilized drug molecules can be absorbed by the cellular membranes to subsequently reach the site of drug action (vascular system for instance).

4. Solubility and Dissolution Intestinal membrane permeability is mostly governed by the chemical structure of a drug. In the current drug discovery and development paradigm, modifications of a chemical structure are performed only during drug discovery. Therefore, a candidate compound must achieve an acceptable intestinal membrane permeability at some point during the drug discovery stage.

5. Solubility and Dissolution In contrast, the dissolution profile can be improved by salt/solid form selection and formulation. The salt/solid form selection and the formulation studies start at the terminal stages of drug discovery.

6. Solubility and Dissolution By many estimates up to 40 per cent of new chemical entities discovered by the pharmaceutical industry today are poorly soluble or lipophilic compounds. These compounds span many therapeutic classes but are often difficult to process or administer to patients due to poor solubility/dissolution properties.

7. Solubility and Dissolution Sugano, Kiyohiko; Okazaki, Arimichi; Sugimoto, Shohei; Tavornvipas, Sumitra; Omura, Atsushi; Mano, Takashi. Solubility and dissolution profile assessment in drug discovery. Drug Metabolism and Pharmacokinetics (2007), 22(4), 225-254.

8. Concepts and Terminology State of the molecule in a medium: –After adding a solid compound into a blank medium, if it looks transparent to the eye, we often say it is ``dissolved'‘ and the medium is typically called a ``solution''. –However, the molecule can exist in this transparent solution as : [1] a monomer (a single molecule surrounded by solvent molecules), [2] a dimer or higher self-aggregate, [3] complexes with large molecules [4] the micelle-included state [5] nano scale particles –In the literature, with the exception of the last case, these are referred as ``solutions'' (the last example is often referred to as a nano-suspension, colloidal dispersion or colloidal solution).

9. Concepts and Terminology Sugano, Kiyohiko; Okazaki, Arimichi; Sugimoto, Shohei; Tavornvipas, Sumitra; Omura, Atsushi; Mano, Takashi. Solubility and dissolution profile assessment in drug discovery. Drug Metabolism and Pharmacokinetics (2007), 22(4), 225-254.

10. Concepts and Terminology Equilibrium solubility: A saturated solution is one in which the solute is in equilibrium with the solid phase (solute). Solubility is defined in quantitative terms as the concentration of solute in a saturated solution at a certain temperature). Solubility is an equilibrium value per se. At equilibrium, the chemical potential of the solid is equal to that of the solution. Martin's physical pharmacy and pharmaceutical science, 5th Ed. By P. K. Sinko.

11. Concepts and Terminology Apparent solubility: In early drug discovery, it is not practical to confirm no change of the concentration and the solid form. However, a long incubation time with intention of reaching equilibrium can beset. After a reasonably long incubation time (typically several hours to a day), the concentration of a compound in the solution which is in contact with the solid is determined as the apparent solubility.

12. Concepts and Terminology Intrinsic solubility: Intrinsic solubility is the solubility of undissociated species of the drug. Intrinsic solubility can be measured at a pH where the compound does not dissociate.

13. Concepts and Terminology Dissolution rate / intrinsic dissolution rate: The term ``good solubility'' often implies the tendency for fast and complete dissolution. If we wanted to be extra accurate, “solubility'' does not imply any kinetic phenomena. “Dissolution rate'' is best used to represent the speed (the dimension is amount/time) The intrinsic dissolution rate is the dissolution rate from a unit surface area of the solid drug (the dimension is amount/area/time), but not the dissolution rate of an undissociated species.

14. Concepts and Terminology Supersaturation: Supersaturation represents a concentration which is higher than the equilibrium solubility. The supersaturation concentration will eventually settle down to match the equilibrium solubility. Supersaturation can occur, for example, in: –Dissolution of salts, meta-stable form, amorphous, and solid dispersion. –pH shift from the high solubility region to low solubility region. –Dilution of a sample solution in a rich solvent (e.g., DMSO) by an aqueous medium.

15. Concepts and Terminology pH: Solubility is often measured by adding a buffer at a pH (“initial pH”) to an excess amount of compound to reach the maximum concentration. In the case of a dissociable compound, the pH can be shifted from the initial pH by the drug. pH has a significant impact on the solubility of weak electrolytes.

16. Concepts and Terminology

17. Solubility/dissolution Enhancement A number of efforts exist to address the issue of enhancing the dissolution of poorly soluble compounds. –Milling techniques –Supercritical fluid processing –Solid solutions and dispersions –Cosolvent formulations –Inclusion complexation –Precipitation techniques –Cryogenic engineering

18. Solubility/dissolution Enhancement Improvement in dissolution performance varies between these techniques. Picking the right technique is not always an easy task, however, the ideal technology should have some basic attributes including: –Simple and favorable regulatory position –Flexible, easily tailored release rates –Low cost –Simple manufacturing procedures –Robustness –Patent protection