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 (colloidal) 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.
Changing the dissolution rate of the
compound
Presenting the compound in solution to
the absorptive process
Wetting agents
Milling techniques
Solid state modifications
Inclusion complexation
Salts/cocrystals
Prodrug (?)
Emulsions / microemulsions
Liposomes
Cosolvent formulations
Self emulsifying delivery systems
Solid solutions and dispersions
Modified after Holm, 2013
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.
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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
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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.
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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.
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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
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