Solvent Systems and Their

Selection in Pharmaceuticals
and Biopharmaceutics

Prof. Agnimitra Dinda

School of Pharmaceutical Sciences
India
 Introduction:
• Solvent systems are integral to drug
development and pharmaceutical technology.
• This single topic encompasses numerous
allied subjects running the gamut from
recrystallization solvents to biorelevant media.
• The goal of this contribution to the
Pharmaceutical Area is to make effective
and informed decisions concerning the use of
solvents and solvent systems.
 Use of Solvent:
• The use of solvents to effect drug substance
crystallization and polymorph selection.
• The use of solvent systems in high throughput
screening and early discovery.
• Solvent use in preformulation.
• The use of solvents in biorelevant dissolution and
permeation experiments.
• Solvents and their use as toxicology vehicles,
solubilizing media and excipients in oral and
parenteral formulation development specialized
vehicles for protein formulation, and solvent
systems for topical and pulmonary drug
administration.
Principles of Solubility:
• Solubility is defined as the maximum quantity of
a substance that can be completely dissolved in
a given amount of solvent, and represents a
fundamental concept in fields of research such
as chemistry, physics, food science,
pharmaceutical, and biological sciences.
• The solubility of a substance becomes especially
important in the pharmaceutical field because it
often represents a major factor that controls the
bioavailability of a drug substance.
• Moreover, solubility and solubility-related
properties can also provide important
information regarding the structure of drug
substances, and in their range of possible
intermolecular interactions.
• For these reasons, a comprehensive
knowledge of solubility phenomena permits
pharmaceutical scientists to develop an
optimal understanding of a drug substance,
to determine the ultimate form of the drug
substance, and to yield information essential
to the development and processing of its
dosage forms.
 Thermodynamics of Solubility:
• The equilibrium solubility of a substance is
defined as the concentration of solute in its
saturated solution, where the saturated solution
exists in a state of equilibrium with pure solid
solute.
• For the particular system of a saturated solution,
the dissolved solute in the solution and the
undissolved solute of the solid phase are in a
state of dynamic equilibrium. Under those
conditions, the rate of dissolution must equal the
rate of precipitation and hence the concentration
of the solute in the solution remains constant
(Temp. Const.).
Dissolution Phenomena: Kinetics of Solubility

• Systemic absorption of a drug substance

from a particulate form takes place after
the compound enters the dissolved state. If
the dissolution rate of the substance is less
than the diffusion rate to the site of
absorption and the absorption rate itself,
then the dissolution process will be the
rate-determining step. This situation is
characteristic of drug substances that have
low degrees of aqueous solubility, and
therefore low dissolution rates.
• Noyes and Whitney (1897) developed an
equation based on Fick’s second law of
diffusion to describe dissolution within the
scope of their model, and report the
relation:
dC DS
---- = ---- (Cs − C)
dt h
 Hixson and Crowell model:
• Hixson-Crowell model is applied to micronized
particles, for which the thickness of the aqueous
diffusion layer around the dissolving particles is
comparable to or larger than the radius of the
particle, the change in particle radius with time
is given by:
2DGst
r2 = r02 - ----------
ρ
• r0 is the initial radius of the particle, r is the radius
of the particle at time equal to t, D is the diffusion
coefficient of the molecules dissolving from the
particle, CS is the equilibrium solubility of the
substance, and ρ is the density of the solution.
 Ionic Equilibria and the pH
Dependence of Solubility:
• Many drug substances can be classified as being
either acids or bases in that they possess the ability
to react with other acids or bases that are stronger
than themselves.
• As such, they would also possess the ability to exist
as ionic species under certain conditions.
• The state of ionization of a substance will often
profoundly affect its degree of aqueous solubility, as
evidenced by the high solubility of sodium benzoate
as opposed to the low solubility of benzoic acid. The
utility of salt forms as active pharmaceutical
ingredients is well known, and represents one of the
means to increase the degree of solubility of an
otherwise intractable substance.
Ionic Solubility Depends on:

• Activity, Activity Coefficients, and the

Equilibrium Constant
• Equilibria of Weak Acids and Bases
• Ionic Equilibria of Acidic and Basic
Substances
• Ionic Equilibria of Buffer Systems
• pH Dependence of Aqueous Solubility
 Solubility in Preformulation:
• Solubility is one of the most important
physicochemical properties studied during
pharmaceutical preformulation.
• For liquid dosage form development, accurate
solubility data are essential to ensure the
robustness of the finished product.
• For solid dosage forms, solubility data are
important in determining if an adequate amount of
drug is available for absorption in vivo.
• If a compound has a low aqueous solubility, it may
be subject to dissolution rate-limited or solubility-
limited absorption within the gastrointestinal (GI)
residence time
 Solubility in MAD:
• Solubility data are also used to estimate the
maximum absorbable dose (MAD)
• MAD is a conceptual tool that relates the
solubility requirement for oral absorption to the
dose, permeability and GI volume and transit
time.
• MAD (mg) = S (mg/mL) × Ka (1/min) × SIWV (mL) × SITT (min)
• where S is solubility at pH 6.5 reflecting typical small
intestine condition; Ka is the trans-intestinal absorption
rate constant determined by a rat intestinal perfusion
experiment; SIWV is the small intestine water volume,
generally considered to be 250 mL; and SITT is the
small intestine transit time, typically about 270 min.
 Solubility Issues in Early Discovery
and HTS (high throughput screening):

• Drug discovery programs begin with target

identification and validation for diseases with
unmet medical needs.
• Compounds that are used in HTS, bioassays
and ADME screening are typically dissolved
and stored in DMSO at a concentration of 10–
30 mM.
 Drug Characteristics into
Biorelevant Dissolution Media
• Oral administration is the most convenient way to
deliver drugs, and therefore the most preferred.
• When moving from the stomach through the pylorus
into the small intestine, the drug will meet a rapidly
changing environment including bile and pancreatic
secretions which will introduce different enzymes
and surface active bile components, and increase in
pH from acidic to neutral.
• An increasing problem for the pharmaceutical
industry, partly arising from the introduction of high
throughput screening, is the discovery of highly
hydrophobic active pharmaceutical candidates with
low water solubility.
 pH ranges in GIT:

• The Stomach - pH ranges between 1.5

and 2.9
• The Upper Small Intestine - pH values
between 6 and 7.1
 Biorelevant Dissolution Media:
• Which media, or combination of media, to
choose, will depend on the
physicochemical characteristics of the
compound, and, when relevant, also on
the type of formulations involved.
• The simplest dissolution media simulating
gastric fluids is the USP test fluid without
pepsin, consisting essentially of 0.1 N HCl
Solvent Systems for Permeability
Screening
• To improve the performance of in vitro
absorption models, a multitude of
approaches have been proposed to
overcome the limitations associated with
classical experimental conditions.
• e.g.
Solubility Enhancers-DMSO
 Solubilizing Vehicles for Oral
Formulation Development
• Drug molecules that are poorly water-soluble can be
difficult to effectively administer in vivo due to
solubility limitations.
• There is a wide selection of solubilizing excipients
that are generally regarded as safe that can be
judicially used to safely and effectively administer
drugs with a wide variety of physiochemical
properties and chemical structures.
e.g. Propylene glycol (PG), medium-chain-
triglyceride, or a mixture such as PEG 400/PG, PEG
400/d-α-tocopherol polyethylene glycol 1000
succinate (TPGS),
 Solubilizing Excipients and
Mixtures:
• Water-Soluble Organic Solvents-polyethylene
glycol 400 (PEG 400), ethanol.
• Surfactants-Polyoxyl 35 castor oil (Cremophor
EL)Polyoxyl 40 hydrogenated castor oil
Cremophor RH40), Polyoxyl 60 hydrogenated
castor oil (Cremophor RH60), Polysorbate 20
(Tween 20), Polysorbate 80 (Tween 80)
• Cyclodextrins- cyclic (α-1,4)-linked
oligosaccharides of α-D-glucopyranose
 Pharmaceutical Solvents as
Vehicles for Topical Dosage Forms
• The selection of a vehicle can dramatically affect
delivery and consequently efficacy of topical
preparations.
• In terms of transdermal delivery, where
delivering therapeutic agents for systemic effects
is desired, solvents and co-solvent systems are
widely used to improve both the amount and
range of drugs that can be administered at
therapeutic levels through the skin.
General Principles for Solvent Selection:
• Thermodynamics
• Vehicle Effects on the Skin
• Biological Factors

Solvents Used As Vehicles:

• Water
• Alcohols
• Ethanol
• Isopropyl alcohol
• Glycols
• Paraffins
• Oleic acid
• Isopropyl myristate
 Conclusion:
Solvent systems are integral to drug development
and pharmaceutical technology. Above discussion
have been designed to cover the theoretical
background of solubility, the effect of ionic equilibria
and pH on solubilization, the use of solvent systems
in high throughput screening and early discovery,
solvent use in preformulation, the use of solvents in
biorelevant dissolution and permeation experiments
and in various formulations.
In addition, trends in the use of solvent systems and
a balance of current views make this monograph
useful.