Molecular Expressions and

Electrolyte Properties of Drug

Molecules

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Physical pharmacy:
• is the branch of pharmacy that concentrates on the
application of physics and chemistry to the study of
pharmacy.
• It emphasis on the physical characteristics and actions
of the drug delivery system before it is given to the
patient.
• It covers areas such as solubility, pharmacokinetics
and drug delivery.
• It serves as principles that guide the pharmaceutical
developments.
• It serves as a basis for the understanding of drug
absorptions, distributions, metabolism, and
eliminations that happen during the course of drug
treatment.
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 The main intended outcomes
The student should be able to:

1. Differentiate between electrolytes and nonelectrolytes and give examples

for each.
2. Differentiate between organic and inorganic acids and bases and give
examples for each.
3. Understand the relation between ionization energy, electron affinity and
electronegativity .
4. Know the main characteristics of group A and transition elements
5. Understand the relation between Pka and drug effects with few
examples of drugs.
6. Solve problems based on the concept of molecular expressions ( moles,
osmoles and Eq) .
7. Solve problems based on the definition of different concentration
expressions.
 Ionization properties of drug
molecules

Nonelectrolytes Electrolytes

Weak electrolytes Strong electrolytes

• According to their ionization properties when dispersed

at the molecular level in an aqueous solution.
• Knowing the composition of the drug based on its
electrolytes properties is very important:
• To avoid mistakes in dosage calculation which may
arise from using the incorrect chemical formula of
the drug in question.
• For example:
– Ephedrine sulfate: 2 protonated Ephedrine
cationic and 1 sulfate anion
– Ephedrine hydrochloride: 1 protonated
Ephedrine cationic and 1 chloride anion

 Both compounds provide the same drug but they have

different molecular weights and thus dose
requirements.
Ephedrine sulphate

Ephedrine hydrochloride
 Non-electrolytes
– Do not possess dissociable ions.
– Important in pharmaceutical preparations.
• Ethanol C₂H₅OH

• Propylene glycol

• Glycerin

• Mono and disaccharides

– Many are freely water soluble.

Inorganic Acids, Bases, and Salts
– The electrolyte Properties governed by element’s
ionization energy and electron affinity.
• Elements are arranged in the periodic table
according to their electron configuration and
trends in ionization potential and electron affinity.

– Ionization energy
• Input of energy required to remove an electron.

• Electron affinity represents the ease with which an

atom can accept an electron.
 Organic acids: CH3COOH
Inorganic acids: HCl, HNO3

Organic Base: CH3-NH2

Inorganic Base: NH3, NaOH,
NH4OH

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 – Electronegativity:
• A measure of the attraction of electron by an atom
in a chemical bond.
•  electronegativity of an atom   its attraction of
bonding electrons.

• The periodic table and ionization energy and electron

affinity:
– Group IA elements (alkali metals) have the lowest
electron affinity and electronegativity.
– Group VIIA elements (halogens) have the highest
electron affinity and electronegativity.
– Group VIIIA elements (noble gases) have zero
electron affinity  they possess a stable octet (He
only two electrons) that cannot accept an additional
electron.
 Ionization energy increase, electron affinity and electronegativity also increase
But atomic radius decrease
increase
electronegativity also decrease, But atomic radius
Ionization energy decrease, electron affinity and
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• Alkali metals:
– Li, Na, K.
– Have one loosely bound electron in their
outermost shell.
– Have low ionization energy.
– They form univalent cations.
– They react with halogens to form neutral salts
(NaCl, KCl).
– They react with water to yield strong
hydroxide bases (LiOH, NaOH, KOH).
– 2Li + 2H2O 2LiOH + H2
• Alkaline earth metals
– Be, Mg, Ca…etc.
– In group IIA in the periodic table.
– Have two electrons in their outermost shell.
– They form divalent cations with halides (CaCl2)
and hydroxide (Ca(OH)2).

• Group IIIA:
– Boron (B) and Aluminum (Al).
– They exhibit different chemical activity.
 +3
– Aluminum metal form trivalent (Al ) with halides
and other anions.
– Boron exhibit both metal and nonmetal
characteristics.
• It is known as a metalloid.
• Can form boron halides (BCl3) similar to those of
aluminum (AlCl3).
• Can act as a non-metal when reacting with sodium.
• Boron form oxide with oxygen (B2O3): this oxide
reacts with water to yield B(OH)3.

– Al(OH)3: is a salt  the OH- are ionic (base).

– B(OH)3: known as boric acid which is an
important pharmaceutical agent in the
preparation of ophthalmic isotonic solutions.
– The OH- are not ionic in B(OH)3 .
Metalloids
• Transition elements: are those elements having a partially filled d or f
subshell in any common oxidation state.
– Groups IB to VIIIB.
– They are all considered metals
– Have low ionization energy.
– May exist in a variety of positively charged forms or oxidation
states…why?
• Because they are capable of losing various numbers of
electrons from their s and d orbitals of their valence shell.

– For example: Manganese (Mn) in group VIIB:

– Mn has 5 unpaired 3d electrons and two 4s electrons. It's highest
oxidation state is +7 when it uses all seven of these electrons.

– Can theoretically have seven oxidation states from +1 to

+7
– In reality, however, it only exhibit +2, +3, +4, +6, +7
• Iron (Fe) can form compounds with +2 and +3 oxidation
states.
• Group VA: N and P
– Occur in the formation of both organic and
inorganic compounds.
– They are key elements for the formation of
various functional groups in organic and
biological chemistry.
– Nitrogen exhibits every integral oxidation number
between -3 ( as in ammonia NH3) and +5 ( as in
nitric acid HNO3).
– In most compounds: Nitrogen has either three
bonds and one unshared electron pair, or four
bonds with no unshared electron pair.
– Example: ammonia and other organic amino
compounds: can accept proton  weak bases.
– Nitric acid on the other hand is an inorganic strong
acid.
– For phosphorus (P):
• The -3 state is far less important than in nitrogen.
• It forms phosphoric acid (H3PO4) with +5
oxidation state: an important weak acid in the
biological system.

• In biological fluids: the most frequently

encountered phosphate ions are H2PO4-1 and
HPO4-2
• Group VIA: O and S
– Form oxides with nearly all other elements except the
rare gases and some noble metals.
– Oxides are divided into three classes:
• Ionic oxides: Li2O and BaO
– Formed by alkali metals and alkaline earth
metals.
– They react with water: form hydroxide (OH-)
ion. Li2O + H2O = 2LiOH
– Alkali metals, they form strong bases.
– Alkaline earth metals, they form weak bases
• Covalent oxides: SO2 and CO2
Formed by elements closer to oxygen in the
periodic table.
 – When CO2 reacts with water: it doesn’t yield a
hydroxide ion but a hydroxide that has a dissociable
proton (acid) CO2 + H2O H2CO3

• Intermediate oxides: Fe2O3 and ZnO

– Many of them do not react appreciably with water.
– They often exhibit characteristics of both acid and
bases: known as amphoteric oxides.

– Oxygen is a key element for the formation of many strong

and weak acids such as:
• Strong acids: nitric acid (HNO3), sulfuric acid (H2SO4)
and perchloric acid HClO4.
• Weak acid: boric acid (B(OH)3), carbonic acid (H2CO3),
carboxylic acids ( compounds with -COOH), phosphoric
acid (H3PO4) and sulfurous acid (H2SO3).
 Extra
• Strong acids
• Weak acids
• Salts are neutralization products of acid-base
reactions. HCl(aq) + NaOH(aq) H2O(l) + NaCl(aq)

• In aqueous solutions:
– Strong acids/bases are completely ionized in dilute
concentrations (HCl and NaOH).
– Weak acids/bases only partially ionized
(CH3COOH, CH3NH2).
• In addition to strong acids and bases, strong
electrolytes (complete ionization in aqueous solutions)
include:
– Salts from the reaction of a strong base with a weak
acid: such as sodium carbonate.
– Salts from the reaction of a strong acid with a weak
base: such as ephedrine sulfate.
• All salts are strong electrolytes.
H2CO + NaOH Na2CO3 + H2O
3
Carbonic acid Sodium hydroxide Sodium carbonate Water

CH3COOH + NaOH CH3COONa + H2O

Acetic acid Sodium hydroxide Sodium acetate Water

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 Organic Acids and Bases
• The majority of pharmaceutical agents are
organic.
• Many classified as weak acids and bases (weak
electrolytes).
• According to Bronsted – Lowry theory:
 Acid: substance (charged or uncharged) that
is capable of donating a proton.
 Base: substance (charged or uncharged) that
is capable of accepting a proton.
• Acid-base behavior affects drug solubility and
chemical stability. 29
 pKa and Drug Effects
• Ka is the acidity constant but often expressed as pKa
for convenience.
pka  - log [ka]
• pKa can be expressed as:

[A ]
pH  pKa  log
[ HA]

• When pH = pKa, 50% of the drug is in the ionized

form.
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• For example: Sulfadiazine
– Weak acid: pKa = 6.3
– The free (neutral) drug is poorly soluble.
– The ionized drug is soluble.
– At normal physiological pH of 7.4: ~90% of the drug
is ionized  ↑ solubility.
– At pH ≤ 6: less that 50% of the drug will be ionized 
↓ solubility.

• A common side effect of sulfa drugs with low

acidity is the crystallization of the free drug and
its N-acetyl metabolites in the renal tubules 
causing kidney damage.
• How to overcome the kidney crystallization
problem?
– Alkalinization of the urine by giving sodium
bicarbonate  reduces crystallization effect.
– Careful selection of drugs based on their pKa
values:
– Sulfisoxazole has a pKa of 5.
– At pH = 6: sulfisoxazole is well ionized (>
90%)  ↑ solubility in body fluids.
– The drug is not deposited in the kidney.
– This drug is a good choice for treating
urinary tract infections as compared to
sulfadiazine.
• Example 2:
– The acidic properties of the cephalosporins derives
from the carboxylic group attached to the bicyclic ring
known as cephem.
– The -lactam moiety of the bicyclic ring is susceptible
to acid-catalyzed hydrolysis  the antibiotics
becomes inactive.
– Cefoxitin:
• Poorly absorbed from the GIT.
• Its poor oral absorption is in part attributed to the
instability of -lactam ring in stomach (acid).
• Must be administered parenterally by IV or IM for
systemic infections.
– Cephalexin:
• It is purposely designed to contain an amino
group at the cephalosporin side chain.
• This base group when ionized form a zwitterion
with the ionized carboxylic group.
• The ionization of the group blocks the acid-
catalysis of the -lactam ring.
• Therefore, Cephalexin is
– Freely soluble in water.
– Resistant to acid.
– Well absorbed orally.
• Example 3: Atropine
– The free drug is not soluble in water.
• It has little use as a pharmaceutical agent.
– The salt that result from reacting atropine free
base with sulfuric acid  atropine sulfate:
• Freely soluble in water.
• Has the same pharmacological effect as the free
drug.
• It is the commercially available form of atropine.
 Molecular Expressions
• Solution
– Multi-component system in which one (or more)
solutes is dissolved in a solvent .
– Important dosage form as drug is dispersed at the
molecular level.

• The Solute
– Solutions can have multiple solutes.
– Quantity of solutes depends on the number of
molecules or ions.

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 Molecular Expressions
• Moles
– Related to Avogadro’s number.
– Calculated by weight of drug/molecular weight.

• Osmoles
– Way to compensate for moles of electrolyte that
undergoes extensive ionization in solution.
– It represent the total number of moles in a solution.
– Osmoles = moles x i. i:van’t Hoff factor

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• Example: if 5 molecules of CaCl2 (strong
electrolyte) were placed in 1 L of water:
– Ionization will result in 5 Ca+2 and 10 Cl-
– The total number of particles = 15
– The number of positive charges = 10
– The number of negative charges = 10
– The net charge of CaCl2 = zero
• Charges:
– The electrolyte property depends on not only the
number of ions generated but also the charge
characteristics of the dissociated ions.
– The quantity that has been used to express the charge
equivalency is the gram-equivalent weight.

weight
gram  equivalent weight (Eq) 
eq weight
where
molecular weight
equivalent weight 
q

q: number of positive (or negative) charges of drug.

 weight of drug x q
Eq 
molecular weight

Eq  moles x q

• Milligram-equivalent weight is also known as

milliequivalent (mEq).

weight of drug x 1000 x q

mEq 
molecular weight

mEq  mmoles x q
• In summary:
– The term mole or millimole is used to express
the number of molecules.
– The term osmole or milliosmole indicates the
total number of particles (including molecules
and ions).
– The term milliequivalent indicates the total
number of positive or negative charges in
solution.
• Example 1: Calculate millimoles, milliosmoles and
milliequivalent contained in 5.55 g of CaCl2 (molecular
weight =111 g/mol).

in water
CaCl  Ca+2 + 2 Cl-
2
i = 3 and q= 2
mmol = 5.55 x 1000 / 111
= 50 mmol

mosmol = 50 x 3 = 150

mEq = 50 x 2 = 100
• Example 2: what are the i and q values for
NaH2PO4, Na2HPO4, NaK2PO4?
• Answer: it depends on the dissociation
– For NaH2PO4:
NaH2PO4  Na+ + H2PO4-
 i = 2 and q = 1

– For Na2HPO4:
Na2HPO4  2 Na+ + HPO4-2
 i = 3 and q = 2

– For NaK2PO4:
NaK2PO4  Na+ + 2K+ + PO4-3
 i = 4 and q = 3
• Example 3: how many milliequivalents of Na+ and
K+ are in 1.96 g of NaK2PO4 ( mol wt = 196 g/mol)

• Answer: for NaK2PO4:

NaK2PO4  Na+ + 2K+ + PO4-3

weight of drug x 1000 x q

mEq 
molecular weight
 1.96 x 1000 x 1
mEq of Na  
 10 mEq
196

1.96 x 1000 x 2
mEq of K 

 20 mEq
196

1.96 x 1000 x 3
mEq of PO 4   30 mEq
196
• Concentrations

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 Concentration units
• Weight or volume concentration
– When the solute is a solid:
– Concentration is often expressed as a weight of
solute in a unit volume of solution.
– For example, w/v % : which is the number of
grams of solute in 100 ml of solution.
– When the solute is also a liquid:
– Concentration may be expressed as the volume
of solute in a unit volume of solution.
– For example: v/v % : the number of ml of solute
in in 100 ml of solution.
 Molarity and molality
– These two similar-sounding terms must not
be confused.
– The molarity of a solution is: the number of
moles of solute in 1 liter of solution.
– The molality is: the number of moles of solute
in 1 kg of solvent.
Interconversion between molarity and
molality requires a knowledge of the
density of the solution.
• In dilute solutions  the volume of the
solution approaches the volume of the
solvent alone  these two concentration
expressions are interchangeable.
• In concentrated solutions  they are
significantly different.
• Mole fraction:
– The mole fraction of a component of a solution is the
number of moles of that component divided by the
total number of moles present in solution.
– In a two-component (binary) solution: The mole
fraction of solvent (x1) is given by
x1 = n1/(n1 + n2)
where n1 and n2 are respectively the numbers of
moles of solvent and of solute present in
solution.

– Similarly, the mole fraction of solute(x2) is given by

x2 = n2/(n1 + n2)

– The sum of the mole fractions of all components is, of

course, unity, i.e. for a binary solution, x1 + x2 = 1.
 Osmolality (or osmolarity)
• This concentration expression is very important for
preparing isotonic pharmaceutical solutions.

• Unlike other concentration terms, osmolality is a

solution property and all solute components contribute
to the osmolality of a solution.

Osmolality (Osm)  m x i

Osmolarity (OsM)  M x i
• Example 4: calculate the osmolality of a solution
that contains in 100 g of the solvent ?
• 0.4 g of NaCl (mol wt = 58.5 g/mol)
• 2.5 g of dextrose (mol wt = 180 g/mol)
• 0.05 g of CaCl2 (mol wt = 111 g/mol)

Colligative properties

wt
xi
Osmolality  mol wt
weight of solvent ( kg )
 0.4 2.5 0.05
x2 x1 x3
Osmolality  58.5  180  111
0.1 0.1 0.1

Osmolality  0.2801 Osm/Kg solvent

• This solution should exhibit the same physical properties

as other solutions having the same osmolality, even if
they contain different solutes.
• In diluted solutions, osmolality ≈ osmolarity.