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.
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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:
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Simple and favorable regulatory position
Flexible, easily tailored release rates
Low cost
Simple manufacturing procedures
Robustness
Patent protection