University of Palestine

College of medicine and health sciences

Clinical pharmacy

Prepared by:
Amal Ahmad Muqbel
120180069
: Supervisor
Dr. Nahed Hegazy
Formation Methods To Enhance/Optimize The Solubility Of
Therapeutic Agents :

1. Drug particle size reduction (micronization):

micronization is employed. Depending on the materials and equipment used,
micronization produces particles ranging from about 1 to 20 mm. [1]

micronization generally leads to higher dissolution rates. For example,

micronization of the poorly water-soluble drugs griseofulvin, chloramphenicol, and
tetracycline resulted in higher dissolution rates when compared with their
nonmicronized forms [2,3]
Micronization has also been used for solubility enhancement of griseofulvin [3],
aspirin [4], and several other drugs. The dissolution rate of hydrophobic drugs can
be further enhanced by the concomitant use of surfactants (e.g., Tween-80) and
hydrophilic polymers [e.g., polyvinyl pyrrolidone (PVP) and polyethylene glycol
(PEG)] as wetting agents, to decrease the interfacial tension and displace adsorbed
air on the surface of solid particles. Micronization sometimes leads to the
unexpected
observation of a decrease in surface area and dissolution rate. This effect is often
due to the aggregation of micronized particles, due to high surface energy and/ or
electrostatic charge, during the micronization process. In such cases, use of
excipients during or after micronization is helpful in reducing aggregation. Thus,
deposition of a micronized drug on an excipient surface can also lead to an
increase in surface area and dissolution. For example, microparticles of nevirapine,
a poorly water-soluble drug, were prepared by supercritical antisolvent method and
deposited on the surface of excipients such as lactose and microcrystalline
cellulose. The nevirapine/excipients mixture showed faster dissolution rate
compared to drug microparticles alone or when physically mixed with the
excipients [5] This could be due to the minimization of aggregation in micronized
drug particles. [6]
1. Loyd V. Allen Jr., Howard C. Ansel - Ansel’s Pharmaceutical Dosage Forms
and Drug Delivery Systems-LWW (2013)
2. Chaumeil JC. Micronization: a method of improving the bioavailability of
poorly soluble drugs. Methods Find Exp Clin Pharmacol 1998;20(3):2115.
3. Reverchon E, Della Porta G, Spada A, Antonacci A. Griseofulvin micronization
and dissolution rate improvement by supercritical assisted atomization. J Pharm
Pharmacol 2004;56(11):137987.
4. Hammond RB, Pencheva K, Roberts KJ, Auffret T. Quantifying solubility
enhancement due to particle size reduction and crystal habit modification: case
study of acetyl salicylic acid. J Pharm Sci 2007;96(8):196773.
5. Sanganwar GP, Sathigari S, Babu RJ, Gupta RB. Simultaneous production and
co-mixing of microparticles of nevirapine with excipients by supercritical
antisolvent method for dissolution enhancement. Eur J Pharm Sci
2010;39(13):16474.
6. Alekha Dash, Somnath Singh, Justin Tolman - Pharmaceutics_ Basic Principles
and Application to Pharmacy Practice-Academic Press (2013).

2. Surfactant :
Substances that absorb to surfaces or interfaces to reduce surface or interfacial
tension. May be used as wetting agents, detergents, or emulsifying agents . [1]
Generally, the longer the hydrophobic chain of a
surfactant, the larger would be the micelles’ size, resulting in greater solubilization.
The solubility of phenobarbital increases more in Tween 80 than in Tween 20,
which contains 12 carbon chain long hydrophobic moiety versus 18 carbon chain
length in Tween 80. Although increased chain length of hydrophilic moiety results
in an overall increase in solubility, the mechanism involved is different from the
size of the
hydrophobic chain length. An increase in chain length of hydrophilic moiety
results in a decrease in micellar size, but the number of micelles per unit volume of
the liquid increases. Therefore, even if drug molecules solubilized per micelle
decrease due to a decrease in size, overall solubility increases due to an increase in
number. For example, solubility of dexamethasone increases in n-alkyl
polyoxyethylene with an increase in oxyethylene number while keeping the alkyl
length [2]

1. Loyd V. Allen Jr., Howard C. Ansel - Ansel’s Pharmaceutical Dosage Forms

and Drug Delivery Systems-LWW (2013)

2. Alekha Dash, Somnath Singh, Justin Tolman - Pharmaceutics_ Basic Principles

and Application to Pharmacy Practice-Academic Press (2013).

3. PH adjustment :
Another technique, if the drug is to be formulated into a liquid product, is
adjustment of the pH of the solvent to enhance solubility. However, for many drug
substances, pH adjustment is not an effective means of
improving solubility. Weak acidic or basic drugs may require extremes in pH that
are outside accepted physiologic limits or that may cause stability problems with
formulation ingredients. Adjustment of pH usually has little effect on the solubility
of substances other than electrolytes. In many cases, it is desirable to use
cosolvents or other techniques such as complexation, micronization, or solid
dispersion to improve aqueous solubility. A review of pH is provided in Physical
Pharmacy Capsule 4.6, Principles of pH. The effect of pH on solubility is
illustrated in Physical Pharmacy Capsule 4.7, Solubility and pH.
pH is one of the most important factors in the formulation process. Two areas of
critical importance are the effects of pH on solubility and stability. The effect of
pH on solubility is critical in the formulation of liquid dosage forms, from oral and
topical solutions to intravenous solutions and admixtures. The solubility of a weak
acid or base is often pH dependent. The total quantity of a monoprotic weak acid
(HA) in solution at a specific pH is the sum of the concentrations of both the free
acid and salt (A−
) forms. If excess drug is present, the quantity of free acid in solution is
maximized and constant because of its saturation solubility. As the pH of the
solution increases, the quantity of drug in solution increases because the water-
soluble ionizable salt is formed. The expression is
HA↔++− Ka
HA where Ka is the dissociation constant. There may be a certain pH level reached
where the total solubility (ST saturated with respect to both the salt and acid forms
of the drug, that is, the pHmax
) of the drug solution is . The solution
can be saturated with respect to the salt at pH values higher than this but not with
respect to the acid. Also, at pH values less than this, the solution can be saturated
with respect to the acid but not to the salt. This is illustrated in the accompanying
figure. To calculate the total quantity of drug that can be maintained in solution at
a selected pH, either of two equations can be used, depending on whether the
product is to be in a pH region [1]

The extent of ionisation of a drug has an important effect on its absorption,

distribution and elimination and there are many examples of the alteration of pH to
change these properties. The pH of urine may be adjusted (for example, by
administration of ammonium chloride or sodium bicarbonate) in cases of
overdosing with amphetamines, barbiturates, narcotics and salicylates, to ensure
that these drugs are completely ionised and hence readily excreted. Conversely, the
pH of the urine may be altered to prevent ionisation of a drug in cases where
reabsorption is required for therapeutic reasons. Sulfonamide crystalluria may also
be avoided by making the urine alkaline. An understanding of the relationship
between pH and drug ionisation is of use in the prediction of the causes of
precipitation in admixtures, in the calculation of the solubility of drugs, and in the
attainment of optimum bioavailability by maintaining a certain ratio of ionised to
un-ionised drug. Table 2.5 shows the nominal pH values of some body fluids and
sites, which are useful in the prediction of the percentage ionisation of drugs in
vivo. [2]

1. Loyd V. Allen Jr., Howard C. Ansel - Ansel’s Pharmaceutical Dosage Forms

and Drug Delivery Systems-LWW (2013)
2. Alexander T. Florence, David Attwood - Physicochemical Principles of
Pharmacy_ In Manufacture, Formulation and Clinical Use-Pharmaceutical Press
(2015).

4. Complexation :
Complexation is the usage of solubilizing complexing agents. There are numerous
types of complexes and some are more water-soluble than others. Coordination
complexes consist of drugs that act as complexing agents (i.e. ligands) and metal
ions (i.e. substrates). Examples of coordination complexes are some water-soluble
tetracycline-metal ion
complexes. [1]
Complexation refers to the interaction of a poorly soluble compound with an
organic molecule (e.g., surface-active agents, hydrophilic polymers) to generate a
soluble intermolecular complex . Cyclodextrins are torus-shaped, cyclic
oligosaccharides consisting of either six (α-cyclodextrin), seven (β-cyclodextrin),
or eight (γ-cyclodextrin) D-glucose units. Owing to their hydrophobic interior,
various cyclodextrins are capable of including a variety of solutes in their interior
cavity. The predominant forces responsible for formation of host-guest complexes
are hydrogen bonding and Van der Waals forces. A derivative of β-cyclodextrin, 2-
hydroxypropyl-β-cyclodextrin (HPβCD) has been found to enhance the solubility
of the antifungal compound, itraconazole (Sporanoxs). Another β-cyclodextrin
derivative, sulfobutylether-β-cyclodextrin (Captisols), has been used to enhance
the solubility of very insoluble, voriconazole (Vfends). The application of another
class of complexing agents, the drug-polymer resin complex, has been identified as
extended-release oral suspensions [2].

1. International Journal of Pharmaceutics, Drug solubilization by complexation

2017
2. Alekha Dash, Somnath Singh, Justin Tolman - Pharmaceutics_ Basic Principles
and Application to Pharmacy Practice-Academic Press (2013).
 5. Solid depression :
A solid dispersion comprises a solid solute dispersed in a solid solvent; it is
designed to provide a system in which the drug is surrounded intimately with
water-soluble material (carrier) and its crystallinity is so altered as to increase its
solubility and solution rate.
In addition to the reduction in crystalline size and hence
an increase in surface area, the following factors may contribute to faster
dissolution rate of drugs in eutectic mixtures:
. an increase in drug solubility because of the extremely small particle size of the
solid
. a possible solubilisation effect by the carrier, which may operate in the diffusion
layer immediately surrounding the drug particle
. absence of aggregation and agglomeration of the particles
. improved wettability in the intimate drug–carrier mixture
. crystallisation in metastable forms

Systems that form eutectic mixtures include chloramphenicol–urea, sulfathiazole–

urea and niacinamide– ascorbic acid
[1]

1. Alexander T. Florence, David Attwood - Physicochemical Principles of

Pharmacy_ In Manufacture, Formulation and Clinical Use-Pharmaceutical Press
(2015)

6. Hydrotropy :

Salts that increase solubility are said to salt in the

solute and those that decrease solubility salt out the solute. Salting out may result
from the removal of water molecules that can act as solvent because of competing
hydration of the added ion. The opposite effect, salting in, can occur when salts
with large anions or cations that are themselves very soluble in water are added to
the solutions of non-electrolytes. Sodium benzoate and sodium p-toluenesulfonate
are good examples of such agents and are referred to as hydrotropic salts; the
increase in the solubility of other solutes is known as hydrotropy.
hydrotropy.Values of k for three salts added to benzoic acid in aqueous solution
are 0.17 for NaCl; 0.14 for KCl; and 0.22 for sodium benzoate. That is, NaCl and
KCl decrease the solubility of benzoic acid, and sodium
benzoate increases it. [1]

1. Alexander T. Florence, David Attwood - Physicochemical Principles of

Pharmacy_ In Manufacture, Formulation and Clinical Use-Pharmaceutical
Press (2015)

7. Microencapsulation:
Microencapsulation is a process of encapsulating microscopic drug particles with a
special coating material, therefore making the drug particles more desirable in
terms of physical and chemical characteristics. A common drug that has been
encapsulated is aspirin. Aspirin has been microencapsulated with ethylcellulose,
making the drug superior in its flow characteristics; when compressed into a tablet,
the drug releases more gradually compared to a simple compressed tablet (Dash et
al, 2010). Usually, biodegradable polymers such as dextran, collagen, chitosan,
poly(lactide), ethylcellulose, and casein are natural materials applied in
microencapsulation. After forming the encapsulation materials as flowing powder,
it is suitable for formulation as compressed tablets, hard gelatin capsules,
suspensions, and other dosage forms (Baracat et al, 2012; Singh et al, 2010). Many
techniques are used in microencapsulating a drug. One process used in
microencapsulating acetaminophen involves suspending the drug in an
aqueous solution while stirring. The coating material, ethylcellulose, is dissolved in
cyclohexane, and the two liquids are added together with stirring and heating. As
the cyclohexane is evaporated by heat, the ethylcellulose coats the microparticles
of the acetaminophen. The microencapsulated particles have a slower dissolution
rate because the ethylcellulose is not water soluble and provides a barrier for
diffusion of drug. The amount of coating material deposited on the acetaminophen
determines the rate of drug dissolution. The coating also serves as a means of
reducing the bitter taste of the drug. In practice, microencapsulation is not
consistent enough to produce a reproducible batch of product, and it may be
necessary to blend the microencapsulated material in order to obtain a desired
release rate. [1]

1. Leon Shargel, Andrew B.C. Yu - Applied Biopharmaceutics &

Pharmacokinetics-McGraw-Hill (2015) .
8. Nanoparticles:
The nanoparticles can be categorized into two main aspects: organic and inorganic.
Organic-based nanoparticles may be composed from biodegradable materials, such
as polylactide (PLA), polyglycolide (PGA), poly(lactideco-glycolide) (PLGA),
polyethylene glycol (PEG), etc, and some biocompatible materials, for example,
poly(propylene oxide) (PPO), polyvinylpyrrolidone (PVP), etc. Inorganic-based
nanoparticles may come from gold, iron oxide, etc. All of them displayed bright
future in the area of controlled drug delivery (Ding et al, 2007, 2011, 2013). In
addition to the large surface area of nanoparticles, surface modification of the
nanoparticles such as binding different chemical groups to the surface with
surfactants or biocompatible polymers (eg, polyethylene glycol, PEG) changes the
pharmacokinetics, toxicity, and surface reactivity of the nanoparticles, in vivo.
Therefore, nanoparticles can have a wide variety of properties that are markedly
different from the same materials in larger particle forms (Couvreur and Vauthier,
2006)
nanoparticles are the first nanomedicine delivery system to make the transition
from concept to clinical application, and they are now an established technology
platform with considerable clinical acceptance (Allen and Cullis, 2013). Table 19-
10 lists the liposomal or lipid-based drug products in the market or still in the
clinical trials. From this table, not only the chemical drugs but also the antibodies,
vaccine, nucleic acids, and gene medicine can be loaded into liposome, for
treatment of infections and for cancer treatment, for lung disease, and for skin
conditions. With surface bioconjugating of targeting molecules on the long-
circulating liposome, the common “passive” liposomal drug delivery system may
evolve to “active” system in the coming future. [1]
Nanoparticles are solid colloidal drug carriers ranging from 101,000 nm in
diameter and are composed of synthetic, natural, or semisynthetic polymers
encapsulating the drug molecule [75]. Many hydrophilic (gelatin, albumin, casein,
polysaccharide lectin, etc.) and hydrophobic polymers (polycaprolactone,
polyesters, polyanhydrides, polycyanoacrylate) are used in the formation of
nanoparticles. Recent biomedical applications include efficient and controlled drug
delivery targeting skin and skin appendages, transcutaneous vaccination, and
transdermal gene therapy. The nanoformulations have modernized conventional
transdermal drug delivery for the treatment of various skin diseases. Nanoparticles
are being used in the field of cosmetics, but there must be a safety assurance and
toxicity check mechanism before application on skin [76].
Solid lipid nanoparticles (SLNs) are composed of a
solid and lipid particle matrix that proves to be an alternative carrier system to
liposomes and emulsions. SLNs exhibit a wide application in the field of
cosmeceuticals and pharmaceuticals due to an increase in the rate of permeation,
occlusion, and hydration of skin. Lipid nanoparticles are formed from
biodegradable lipids, which are used as safe carriers with excellent tolerability.
Cosmetic companies rank high among nanotechnology patent holders in the United
States;L’Oreal, which devotes about $600 million of its annual $17 billion
revenues to research, is the industry leader on nanopatents [2]

1. Leon Shargel, Andrew B.C. Yu - Applied Biopharmaceutics &

Pharmacokinetics-McGraw-Hill (2015)
2. Alekha Dash, Somnath Singh, Justin Tolman - Pharmaceutics_ Basic Principles
and Application to Pharmacy Practice-Academic Press (2013)

9. Salf formation:

The dissolution rate of a salt form of a drug is generally quite different from that of
the parent compound. Sodium and potassium salts of weak organic acids and
hydrochloride salts of weak organic bases dissolve much more readily than do the
respective free acids or bases. The result is a more rapid saturation of the diffusion
layer surrounding the dissolving particle and the consequent more rapid diffusion
of the drug to the absorption sites. Numerous examples could be cited to
demonstrate the increased rate of drug dissolution due to the use of the salt form of
the drug rather than the free acid or base, but the following will suffice: The
addition of the ethylenediamine moiety to theophylline increases the water
solubility of theophylline fivefold. The use of the ethylenediamine salt of
theophylline has allowed the development of oral aqueous solutions of
theophylline and diminished the need to use hydroalcoholic mixtures such as
elixirs. [1]

1. Loyd V. Allen Jr., Howard C. Ansel - Ansel’s Pharmaceutical Dosage Forms

and Drug Delivery Systems-LWW (2013)

10. Nanosuspension:
In nanosuspensions, the particle sizes of the dispersed particles in the suspensions
are in the nano range. These systems have an advantage of higher mass-to-volume
loading. Therefore, nanosuspensions are useful when there is a higher dosing
requirement. For intramuscular or ophthalmic delivery in which there is a need for
low administration volume, a nanosuspension is a better choice because of high
drug loading in the nanosuspension.
A number of drugs using the nanosuspension technique are in the market as well as
in clinical trials. [1]

2. Alekha Dash, Somnath Singh, Justin Tolman - Pharmaceutics_ Basic

Principles and Application to Pharmacy Practice-Academic Press (2013)

11. permeation enhancers:

There is great interest among pharmaceutical scientists to develop chemical
permeation enhancers and physical methods that can increase percutaneous
absorption of therapeutic agents.
Some drugs have an inherent capacity to permeate the skin without chemical
enhancers. However, when this is not the case, chemical permeation enhancers
may render an otherwise impenetrable substance useful in transdermal drug
delivery . More than 275 chemical compounds have been cited in the literature as
skin penetration enhancers; they include acetone, azone, dimethylacetamide,
dimethylformamide, dimethyl sulfoxide, ethanol, oleic acid, polyethylene glycol,
propylene glycol, and sodium lauryl sulfate . The selection of a permeation
enhancer should be based not only on its efficacy in enhancing skin permeation but
also on its dermal toxicity (low) and its physicochemical and biologic
compatibility with the system’s other components [1]
A variety of excipients known as absorption enhancers or permeation enhancers
have been incorporated into the drug product to promote systemic drug absorption
from the application site. For oral drug products that contain poorly absorbed
hydrophobic drugs, surfactants have been added to the formulation to help
solubilize the drug by making the drug more miscible in water. The stratum
corneum is the major barrier to systemic drug absorption from transdermal drug
products. The addition of excipients or the use of physical approaches has been
used to enhance drug permeation from transdermal products. For example,
Estraderm®, a estradiol transdermal system, contains ethanol, which promotes
drug delivery through the stratum corneum of the skin. The use of ultrasound
(phonophoresis or sonophoresis) has been used by physical therapists to enhance
percutaneous absorption of hydrocortisone ointments and creams from intact skin.
Iontophoresis is a technique using a small electric charge to deliver drug
containing an ionic charge through the stratum corneum. Most of these absorption
enhancement approaches attempt to disrupt the cellular barriers to drug transport
and allow the drug to permeate better. [2]

1. Loyd V. Allen Jr., Howard C. Ansel - Ansel’s Pharmaceutical Dosage Forms

and Drug Delivery Systems-LWW (2013)
2. 1. Leon Shargel, Andrew B.C. Yu - Applied Biopharmaceutics &
Pharmacokinetics-McGraw-Hill (2015)
 12. Prodrug formation:
Prodrug is a term used to describe a compound that requires metabolic
biotransformation after administration to produce the desired pharmacologically
active compound. The conversion of an inactive prodrug to an active compound
occurs primarily through enzymatic biochemical cleavage. Depending on the
specific prodrug–enzyme interaction, the biotransformation may occur anywhere
along the course of drug transit or at the body site where the requisite enzymes are
sufficiently present. An example of a prodrug is enalapril maleate (Vasotec),
which, after oral administration, is bioactivated by hydrolysis to enalaprilat, an
ACE inhibitor used in the treatment of hypertension. Prodrugs may be designed
preferentially for solubility, absorption, biostability, and prolonged release .
Solubility A prodrug may be designed to possess solubility advantages over the
active drug, enabling the use of specifically desired dosage forms and routes of
administration. For example, if an active drug is insufficiently soluble in water to
prepare a desired intravenous injection, a water-soluble prodrug, for example,
hydrocortisone sodium succinate, could be prepared through the addition of a
functional group that later would be detached by the metabolic process to yield,
once again, the active drug molecule. [1]
prodrug is defined as any compound that undergoes biotransformation before
exhibiting pharmacological effects. Prodrugs are considered to be inactive or at
least less significantly active than the released drugs. Once inside the body, these
prodrugs undergo enzymatic or chemical reaction to show drug-like properties
(i.e., absorption, distribution, metabolism, and excretion). The transformation of a
prodrug to actual drug behavior is schematically shown in Figure 12.25. Note the
“barrier” shown in Figure 12.25. Prodrugs
provide possibilities to overcome various barriers to drug formulation and delivery,
such as aqueous solubility, chemical instability, insufficient oral absorption, rapid
presystemic metabolism, insufficient penetration into the brain, toxicity, local
irritation, and patient compliance such as odor and taste [60]. The design of the
prodrug structure is considered in
the early phase of clinical development. This will include the appropriate
functional groups (promoiety) for derivatization. Promoiety should be safe and
rapidly excreted from the body. The choice of promoiety should be appropriate for
the disease state. Some of the common functional groups used in prodrug design
are carboxylic, hydroxyl, amine, phosphates, and carbonyl groups. [2]
1. Loyd V. Allen Jr., Howard C. Ansel - Ansel’s Pharmaceutical Dosage Forms
and Drug Delivery Systems-LWW (2013)
2. Alekha Dash, Somnath Singh, Justin Tolman - Pharmaceutics_ Basic Principles
and Application to Pharmacy Practice-Academic Press (2013) .