Solubility and Dissolution Selected Topics in Pharmaceutical Technology

Number of publications containing the concept “poor solubility drug”

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 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 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 a variety of formulation technolgies.

Concepts and Terminology State of the molecule in a medium: After adding a solid compound into a blank olvent, if it looks transparent to the eye, we often say it is ``dissolved'‘ and the product 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 equilibrium 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 equilibrium 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. Intrinsic solubility is a critical concept in determining the BCS class of a compound. Definition of a dose number ??

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.

Solubility/dissolution Enhancement A number of efforts exist to address the issue of enhancing the dissolution of poorly soluble compounds. Presenting the compound in solution to the absorptive process Changing the dissolution rate of the compound Emulsions / microemulsions Liposomes Cosolvent formulations Self emulsifying delivery systems Wetting agents Milling techniques Cryogenic engineering Supercritical fluid processing Solid state modifications Inclusion complexation Precipitation techniques Salts/cocrystals Prodrug (?) Solid solutions and dispersions Modified after Holm, 2013

Biopharmaceutical classification system (BCS) of drugs Biopharmaceutical classification system (BCS) of drugs. If a class II drug can be maintained in a solubilized state in the gut lumen one can achieve an absorption profile comparable to that of a Class I compound. The best solution to improve the bioavailability of BCS Class IV and III is to go back to the lead optimization phase of drug discovery to modify their chemical structures and select a candidate with more appropriate physicochemical properties. (Klein, 2013)

Dressman et al., 2011. HA.PT

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

Energetics of Solubility HA.PT

Brick Dust or Grease Ball To solve the problem of poor solubility/dissolution of a drug through prodrug formation we must understand the reason why is the compound exhibiting poor solubility: Is the molecule one that displays high crystallinity, a “brick dust” molecule, or is it a low melting or “grease ball” molecule? Obviously, a continuum exists, with most molecules not fitting either extreme. HA.PT

Brick Dust or Grease Ball Grease ball molecules: Highly lipophilic compounds with a high log P (> 4) and a low melting point (< 200 °C). These compounds cannot form bonds with water molecules, thus, their solubility is limited by the solvation process. Brick dust molecules: Are usually compounds with a high melting point (> 200 °C) and a low log P (< 2). The solubility of the compounds in water is restricted due to strong intermolecular bonds within the crystal structure. HA.PT

Brick Dust or Grease Ball If the molecule has the characteristics of a “grease ball” molecule and usual formulation approaches do not work, solubility enhancement through the use of a polar promoiety may prove useful. If one has a “brick dust” molecule a polar promoiety may work, as might strategies that disrupt the intermolecular interactions that led to the high crystallinity HA.PT