Solubility and Dissolution Pharmaceutical Technology

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

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).

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

Concepts and Terminology

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

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