PHARMACEUTICAL CHEMISTRY (SECOND YEAR)

MEDICINAL AGENTS FOR CONTROL OF PH

 When the PH of the body deviates from normal (PH 7.4 of plasma), it may result to hypo or
hyperacidity. The closer the PH is to 7.4, the higher the level of health and well being and the
ability to resist diseases.
 The human body constantly fights to maintain a body PH of 7.4.

BODY RESPONSES THAT MAINTAIN PH

 WATER- in this case the body uses water as a solvent to neutralize acid residues.
 Pulling bicarbonate ions from the pancreas into the blood. In this case, the bicarbonate ions act as
alkalinizing agents. They are generated into the blood cells from carbon dioxide and diffuse into
plasma.
 Protein buffers of glutathione , methionine, cysteine act as buffers intracellularly to bind or
neutralize acid during cellular disorganization
 Electrolyte buffers of sodium, calcium and potassium work in the blood lymph and intracellular
fluids to bind acids which are then removed through the urine.
 Filtration and elimination of acidic and basic residues through the skin , urinary tract and
respiration
 Pulling stored calcium and magnesium from skeletal bones and teeth to neutralize blood acids
 Pushing blood acid and base residues and accumulated toxins into outer extremities away from
vital organs. The wrist, joints, fingers, toes and skin are the major target areas to keep toxins from
saturating internal vital organs e.g. heart and lungs.

DEFINITIONS RELATED TO CHANGES IN BODY PH

 When the PH of the body deviates from the normal, the condition is normally described in terms
of acidity. This can be divided into;
I. HYPERACIDITY-This is when the acidity is higher than normal.
II. HYPOACIDITY- This is when the acidity is lower than normal
 Abnormalities of acidity in the human body can further be divided into:
I. Gastric and intestinal abnormalities.
A. This can either be gastric hyperacidity, ingestion of acidifying salts such as
ammonium chloride and calcium chloride which results in the addition of
hydrochloric acid to the body. Gastric hyperacidity is much more common and
familiar to many.
B. Gastric hypoacidity- medically referred to as achlorhydria. This could result
from loss of acid from the body as a result of severe vomiting of gastric juice
which is rich in HCl(PH 3.4)
II. Systemic abnormalities
A. Systemic hyperacidity-This is normally referred to as acidosis. Common
sources of extra acid include:
 Strenuous exercise(lactic acid)

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  Diabetic ketoacidosis
 Failure of diseased kidneys to excrete normal amounts of acid.
B. Systemic hypoacidity which is commonly referred to as alkalosis. The body’s
homeostasis mechanism for systemic alkalosis is through urinary excretion of
dihydrogen phosphate ion. Therefore the PH of urine varies depending on
systemic acidity

Medicinal agents of importance in terms of control of PH are divided into:

1. Gastric antacids used for controlling GIT hyperacidity

2. Systemic antacids and drugs used in systemic acidosis
3. Drugs used in achlorhydria and hypochlorhydria
4. Urinary acidifiers and drugs used to treat antacid induced alkalosis.

ACHLORHYDRIA AND HYPOCHLORHYDRIA

 Achlorhydria is where HCl is absent and production of gastric acid is absent. Hypochlorhydria is
where HCl is lower than normal
 The conditions may be due to ;
o Overuse of antacids
o Autoimmune disorders where antibodies are produced against the parietal cells
o Stomach cancer
o Atrophic gastritis
 Treatment is by use of:
o Acids
o Acidifying agents e.g. ammonium chloride and calcium chloride.

GASTRIC ANTACIDS AND ANTACID ACTION

1. Gastric acid of a normal fasting person has a PH value of between 0.9- 1.5. However, under
certain conditions e.g. PUD this level of acid is irritating and corrosive. In such a case, it is
necessary to reduce acidity by using a suitable antacid.

Chemistry of Antacids

 It involves reduction of hydroxonium ion concentration with a base stronger than water.

H3O + + B- HB + H2O
Weak acid Weak base
Strong acid Strong base

 The stronger base which is an antacid favors the forward reaction. If water was stronger, then the
backward reaction would be favoured.
 The product of neutralization is a weak base and a weak acid with optimum PH. The desirable PH
to be attained after antacid action is about 3.5-4.0. Any neutralization going beyond this range is

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 undesirable. If attained PH goes above 4; it will interfere with gastric digestion and increase
possibility of inducing acid rebound.
 As the stomach content becomes less acidic, the gastric glands tend to increase secretion of HCl
in an effort to restore normal gastric PH. If this occurs, then the desired effect of gastric antacid is
counteracted and thus reduced. The greater the PH shift of antacid action, the greater the chances
of acid rebound. The appearance and extent of this rebound phenomenon depends on;
o Nature of antacid and its reaction by-product
o Individual variations of the patient.

Some antacids when ingested in excess have a continued antacid action and gastric PH shift beyond the
desirable range e.g. the following reaction takes place when NaHCO 3 is ingested in excess.

H3O+ + HCO3- H2CO3 + H 2O

Weak acid

H2CO3 + CO2 + H2O

The CO2 produced is responsible for burps experienced with ingestion of NaHCO 3 . When all the
hydronium ions have been consumed, the following reaction takes place.

HCO3- + H2O H2CO3 + OH-( basic)

In pure water, the above reaction can move to a PH of 8 or slightly higher but in the presence of other
substances in the stomach, it rarely exceeds a PH of 7. Other antacids which are insoluble do not exhibit
the above neutralization reaction e.g. aluminium hydroxide which is only soluble in acidic media. Its
neutralization reaction proceeds in a series of steps depending on the amount of antacid ingested and on
gastric PH.

Al(H2O)3(OH)3 + H3O+ [Al(H2O)4(OH)2]+ + H2O

[Al(H2O)4(OH)2]+ + H3O+ [Al(H2O)5(OH)]2+ + H2O

[Al(H2O)5(OH)]2+ + H3O+ [Al(H2O)6]3+ + H2O

Hexaqua-aluminium

AS acidity of gastric acid decreases on consumption of Hydronium ion in the above reaction, the rate of
dissolution and reaction of the base with H30+ also decreases. This neutralization proceeds at this
decreasing rate until a PH is reached at which the antacid is completely insoluble or its solution is so low
that for practical purposes the reaction stops.

 Aluminum hydroxide is insoluble in alkaline media but soluble in acidic. The hexaqua-aluminium
ion is a weak acid which corresponds to a PH of 4. The excess undissolved aluminium hydroxide
has virtually no effect on the equilibrium of the reaction.
 If the action of an antacid is limited to the GIT , then it is referred to as non- systemic
antacid(Gastric antacid). These antacids include:
o Insoluble anions e.g. CO3-, PO43-and OH-

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 o Oxides or silicates of cations of Al, Mg, Ca, Bi
 Antacids which affect the PH of all body fluids and to some extent the GIT are referred to as
systemic antacids. They act by increasing the amount of bicarbonate levels of the blood and body
fluids.The reaction is normally through the change of base/acid ratio of the HCO 3- buffer system.
[Base ]
o PH = Pka + log pka of HCO3- is 6.4
[ Acid ]
 When this occurs, a general systemic alkalosis occurs depending on the amount of antacid
ingested and the frequency of administration. In an effort to restore the rise in bicarbonate ion
levels, more bicarbonate will be lost through the urine hence there will be production of alkaline
urine. As a result, systemic antacids are also called urine alkalinizers.
o HCO3- + H2O H2CO3 + OH-
o The above reaction is not extensive but is sufficient to cause a definite alkaline shift in
urine acidity. All systemic antacids are water soluble and they include the following
compounds of sodium and potassium
 HCO3-
 Acetates
 Citrates
 The above organic anions have a delayed systemic antacid effect. Initially, they exert a gastric
antacid effect.
o In the GIT H3O+ + B- HB + H2O
o Since intestinal mucosa is permeable to both neutralized antacid and any excess un
neutralized antacid, both find their way into the blood stream. Acetates, citrates and their
ions being constituents of normal carbohydrates oxidative mechanisms are converted to
an equivalent quantity of HCO3-. The blood levels of bicarbonate increases which
therefore results in alkalosis.

COMPOUNDS USED AS ANTACIDS

They are divided into:

a. soluble compounds
b. Insoluble compounds

SOLUBLE COMPOUNDS

 Contain K+/Na+ based cations.

 Anions involved include HCO3-, acetate, citrates.
 Are capable of producing systemic alkalosis as well as urinary alkalosis.

INSOLUBLE COMPOUNDS

 Contain Mg2+/Al3+/Ca2+/Bi3+ cations

 Anions are strong bases as opposed to the weak bases used in soluble antacids. Anions
include CO32- ,PO43- , OH- ,O2-, Trisilicates.

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  E.g. Mg( oxide, hydroxide, trisilicate, carbonate, phosphate) and Ca( carbonate,
phosphate)

In both the soluble and insoluble compounds, the anion acts as a abase and is responsible for the
antacid action

The cation controls the antacid activity of the anion. The cation does this by controlling the
solubility of the compound e.g. OH- has an excellent antacid activity because it’s a strong base but
in practice, its usefulness is limited to a few compounds whereby its solubility is controlled by a carefully
selected cation.

NaOH is too soluble to be a useful antacid. It releases a very high [OH -] which renders it excessively
corrosive.

But when the OH- is formulated from Mg/Al, the compounds formed are useful antacids. The solubility
of Al(OH)3 and Mg(OH)2 is a constant. The OH- ions are released in low concentrations at a time hence
too low to cause corrosion. These compounds therefore act as excellent antacids. From the discussion
based on the cation of the anion, a given antacid has two aspects to be considered.

a) Anionic properties
b) Cationic properties

ANIONS AS BASES FOR THE ANTACIDS

 For the soluble antacids , they employ weak anions and they include
1. ACETATE- acetate ions and acetic acids are absorbed readily from the GIT with no
metabolic problem occurring.
a. CH3COO- + H3O+ CH3COOH + H2O
b. CH3COO- + H2O CH3COOH + OH-

The acetate ions and acetic acid are oxidized to an equivalent quantity of bicarbonate ions in the normal
carbohydrate oxidative mechanism. Because of its absorption and conversion to bicarbonate ions, the
acetate ions always act as systemic antacid hence used as gastric antacid. For this reason, the acetate ion
is administered when systemic acidosis is to be corrected. The acetate ion is formulated as potassium or
sodium salts and both salts have a diuretic effect.

2. Citrate -The citrate ion is slightly stronger than the acetate ion. It is absorbed in the GIT and in
ordinary quantities, it is oxidized to the equivalent bicarbonate ion quantities e.g. citrosoda.
Citrosoda is a typical preparation available in the market. It is an effervescent formulation of
citric acid and sodium bicarbonate in powder form. The product has both gastric antacid action as
well as systemic antacid action.

Bicarbonate is an effective antacid that is used commercially and domestically.

NaHCO3 Na+ + HCO3-

HCO3- + H3O+ H2CO3 + H2O

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H2CO3 H2O + CO2

HCO3- + H2O H2CO3 + OH-

DISADVANTAGES OF CITROSODA

1. Evolution of carbon dioxide

2. Production of sodium hydroxide which will have a systemic effect. Because of systemic
involvement, citrate like the acetate ion is rarely employed as a gastric antacid. In large doses, it
has a secondary action which increases the flow of various secretions including urine. However
citrate ion is sometimes used for its gastric antacid action. In this case, it is commonly present to
protect a simultaneously administered medicine especially which can be decomposed by the acid
medium of the stomach e.g. some penicillin. Palatability of the citrate is superior to that of the
acetate ion.

Bicarbonate is an effective antacid which is widely used.

Although widely used, bicarbonate ion has two main disadvantages;

 The systemic action produced may be undesirable especially if used repeatedly as a gastric
antacid in self medication.
 There is evolution of carbon dioxide gas which can result in discomfort because of the undue
distension of the stomach and the intestines.

Bicarbonate ion should not be used as antidote in accidental ingestion of strong acids. This is because the
CO2 produced may lead to perforations of the stomach and in due course peritonitis. The gas produced
can be dangerous to patients with ulcerations.

FOR INSOLUBLE ANTACIDS, STRONG ANIONS ARE USED AND THEY INCLUDE;

1. THE CARBONATES
1. The carbonates can only be formulated as the insoluble form.
2. The carbonate ion is such a strong antacid that it cannot be formulated in the soluble
form. For this reason, sodium and potassium are not formulated in the form of
carbonates.
3. However, carbonates can be formulated in the form of calcium, magnesium,
aluminium and Bismuth.
CaCO3 CaCO3 Ca2+ + CO32-
Undissolved Dissolved
CO32- + H3O+ HCO3- + H2O

HCO3- + H3O+ H2CO3 + H2O

H2CO3 H2O + CO2

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Upon consumption of all hydronium ions, the reaction stops. For this reason, the insoluble carbonate
antacids do not impart excess alkalinity to the intestinal content.

The carbonate ion like the bicarbonate ion also involves the production of carbon dioxide gas which is a
disadvantage because it causes distension of the stomach and discomfort as well as the burp. However
unlike the bicarbonate ion, the carbonate ion has no systemic antacid action if used in moderation.

2. HYDROXIDES
1. The most common hydroxides are those of aluminium and magnesium.
2. This category also incorporates magnesium trisilicate, bismuth and aluminium
glycinate( aminoacetate). Just like the carbonates, soluble hydroxides are not used as
antacids e.g calcium hydroxide.
3. In combination with the appropriate cation, hydroxides have excellent antacid properties.
The excellent antacid properties of these bases depend on their solubility product which
controls the release of the hydroxyl ion from the insoluble compound.
4. The reaction proceeds as long as the hydronium ion is available to react with the
dissolved hydroxyl ion

Mg(OH)2(Undissolved) Mg(OH)2(dissolved)

Mg(OH)2(dissolved) [Mg(OH)]+ + OH-

OH- + H3O+ 2H2O

[Mg(OH)]+ Mg2+ + OH-

[Mg(OH)]+ + H3O+ Mg2+ + 2H2O

The magnesium cation also has laxative effect. The hexaaquaaluminium cation [Al(H2O)]3+ can cause
constipation.

3. THE OXIDES

MgO (Insoluble) + H3O+ [Mg(OH)]+ + H2O

[Mg (OH)]+ Mg2+ + OH-

OH- + H3O+ 2H2O

Since the reaction stops when the equilibrium is reached, the hydroxyl ion concentration is allowed by the
solubility product and when this ionic product of water has reached equilibrium. Therefore the antacid
action of this compound is self limiting i.e. automatically stops. The dissolved cations resulting from
antacid action react with bicarbonate present to form insoluble carbonate in the alkaline media of the

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 intestines. They are then eliminated in the faeces.When used in moderation; this group of antacid has no
systemic effect. The tribasic magnesium trisilicate belongs to the hydroxide/oxide group in the antacid
action

2MgO.3SiO2.3H2O

SiO2 + 2H2O H4SiO4 ( Silicic acid)

MgO + H2O+ Mg2+ + 3H2O

Magnesium trisilicate is essentially a mixture of hydrated magnesium oxide and silicic acid. The antacid
action is due to the insoluble magnesium hydroxide and the hydrated magnesium oxide present.The silicic
acid does not participate in antacid action except to a very limited extent by adsorption of hydronium ion.

Silicic acid is gelatinous and has a protective action in the intestinal lining.

4. PHOSPHATES
 They include aluminium phosphate, calcium phosphate and magnesium phosphate.
 The tertiary phosphate ion is a powerful base which is present in aqueous solutions. It produces
one hydroxyl ion in each subsequent ionization i.e. each phosphate ion will give an equivalent
amount of hydroxyl ions. The solubility of the insoluble phosphate ion will determine the extent
at which the reaction will proceed,

Ca3(PO4)2 Ca3(PO4)2 (Aqueous)

undissolved

Ca3(PO4)2 3Ca2+ + 2PO43-

PO43- + H2O HPO42- + OH-

HPO4- + H2O H2PO42- + OH-

Antacids are available in the form of systemic and gastric antacids.

Antacid activity is based on the accompanying anion.

The acetate, citrate and bicarbonate ions are formulated as the soluble ones while the carbonates,
hydroxides, oxides, and phosphates are formulated as the insoluble antacids.

Acid-base incompatibilities result when bicarbonates, acetates or citrates are used in solution. Hence they
are formulated as effervescent preps.

The carbonates, hydroxides, oxides and phosphates are formulated as insoluble antacids. The solubility of
the soluble and insoluble antacids will determine the degree and extent of the antacids action.

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ALUMINIUM BASED

 Most popular class of antacids. Aluminium is commonly formulated with other antacids
preferably magnesium. The purpose of combination is mainly to;
i. Overcome some of the undesirable effects associated with aluminium cation that result
following antacid action.
ii. Make the formulation have a faster onset of action with a longer duration of action.
 Common bases formulated with aluminium include:
i. Hydroxides Al(H2O)3(OH)3
ii. Carbonates [Al(H2O)4(OH)2]+.CO32-
iii. Phosphates AlPO4
iv. Aminoacetate [Al(H2O)4(OH)2]+.NH2COO-

MODE OF ACTION OF ALUMINIUM HYDROXIDE

The overall mode of action of a given aluminium based antacid is a function of the anion present.

Al (OH)3 + 3H2O [Al(H2O)2(OH)3]0

1. [Al(H2O)3(OH)3]0 + H3O+ [Al(H2O)4(OH)2]+ + H2O

2. [Al(H2O)4(OH)2]+ + H3O+ [Al(H2O)5(OH)]2+ + H2O
3. [Al(H2O)5(OH)]2+ + H3O+ [Al(H2O)6]3+ + H2O

The Pka of the hexaaquaaluminium cation is 4.85.It is unlikely that the third reaction proceeds to
completion since the dissolved aluminium hydroxide ions are no longer neutralized as they separate from
the solid .This reaction automatically stops. The reaction is self limiting.

The second and third reactions are responsible for at least half of the antacid action of the basic aluminum
carbonate and the dihydroxyaluminium aminoacetate. However, reaction 1 does not contribute any
antacid action for the latter two compounds i.e. aluminium carbonate and the dihydroxyaluminium amino
acetate. This is because the first reaction takes place prematurely during their preparation.

The anions present in these two compounds i.e. the carbonate and the aminoacetate provide additional
neutralizing capacity. For aluminum carbonate, it undergoes reaction 2 and 3 in a similar way to
aluminium hydroxide.

4. CO32- + H3O+ HCO3- + H2O

5. HCO3- + H3O+ H2CO3 + H2O
6. H2CO3 H2O + CO2

The antacid effect of the carbonate ion is as shown above (from reaction 4-6). All the antacid effect of the
carbonate ion will go to practical completion before reaction 3 is complete i.e. equilibrium reaction 4-6
will be complete before reaction 3.

DIHYDROXYALUMINIUM AMINOACETATE/Aluminium glycinate

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2. [Al (H2O) 4(OH) 2)+. NH2CH2COO- + H3O+ [Al (H2O) 5(OH)] 2+ + H2O

3.[Al (H2O) 4(OH) 2)]2+. NH2CH2COO--+ H3O+ [Al (H2O) 6]3+ + NH2 CH2COO- + H2O

4.NH2CH2COO- + H3O+ NH2CH2COOH + H2O

(aminoacetic acid)

5.NH2CH2COOH + H3O+ NH3+CH2COOH + H2O

(Protonated amino acid)

Similarly, the aminoacetate ion is a stronger base and so it will be protonated before reaction (III) can
take place. Reaction (IV) will take place before reaction (III).

Theoretically, reaction 5 is possible, however,the aminoacetic acid is a weaker base than the cation in
reaction(III). Hence reaction 5 may not take place unless the aminoacetic acid is in large quantities. This
is called the mass effect

ALUMINIUM PHOSPHATE

 It is a three positive and three negative type of electrostatic compound. This makes
aluminium phosphate an extremely insoluble substance.
 Aluminium phosphate is also insoluble in acetic acid but soluble in strong mineral acid
(HCl, H2SO4).
 Depending on the amount allowed by its solubility constant, it will dissolve to give the
hexaaquaaluminium ion and the tertiary phosphate.
1. AlPO4 + 6H2O [Al(H2O)6]3+ + PO43- ( tertiary phosphate).
2. PO4 + H3O
3- +
HPO42- + H2O
Tertiary Monohydrogen
phosphate phosphate

The tertiary phosphate is an extremely strong base and therefore the above reaction (2) will proceed to
completion. In addition, the monohydrogen phosphate ion can undergo the following reaction.

3. HPO4- + H3O+ H2PO4- + H2O

Dihydrogen phosphate

The cycle of reactions can continue until the PH of the gastric contents is corrected to the levels at which
aluminium phosphate is no longer sufficiently soluble to provide the anion necessary for antacid action.

4. H2PO4- + H3O+ H3PO4 (phosphoric acid)+ H2O

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ADVANTAGES AND DISADVANTGES OF ALUMINIUM BASED ANTACIDS

The dissolved aluminium cations impact certain characteristics to the compounds.

1. Since they are poorly absorbed due to the cation not moderating solubility, the aluminium
compounds have no or little systemic antacid action
2. Aluminium cations impart astringent and an antiseptic action to the intestinal fluid. The astringent
effect interferes with water excretion from the blood vessels in the intestinal mucosa. This water
is important in the formation of soft stool.
3. The aluminium cation action is responsible for constipation effect hence if used in excess over
prolonged periods of time can cause obstinate constipation
4. The aluminium antacids with the exception of aluminium phosphates interfere with the
absorption of phosphate ions from food.

[Al(H2O)5(OH)]2+ + HPO42- AlPO4 + 6H2O

(In food)

Monohydrogen
phosphate

The alkaline media of the small intestines favors the precipitation of the insoluble aluminium phosphate.
Because of the abundance of phosphates in food, this effect can only occur with prolonged use of the
aluminium antacids. However this effect can be overcome by ensuring that one has a daily intake of about
750 mg 0f phosphates.

5. Insoluble aluminium gel esp. the hydroxides are good adsorbing agents and if used continuously
and over a long period of time, deficiencies of trace elements (food substances) may develop.
Concomitant administration of antibiotics may prove valueless due to adsorption of the drugs on
the aluminium gel.
6. ALUMINIUM HYDROXIDE
a. It is widely used for treatment of PUD. Its neutralizing action is controlled by its
insolubility, therefore does not cause acid rebound phenomenon.
b. Because of the presence of unreacted solid phase, the neutralizing action of aluminium
hydroxide is available over a long period of time.
c. Aluminium hydroxide has an inhibitory action on pepsin even under acidic conditions.
d. The gelatinous nature of the unreacted solid gives the preparation some protective
action on gastric and intestinal mucosa.
e. Aluminium hydroxide is frequently administered as an adjunct therapy with some
medications. It has the effect of relieving the distress encountered during
administration of long term medication e.g. NSAIDs esp. with high doses encountered
in rheumatology

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 i. Aluminium hydroxide can be simultaneously administered with some drugs is
used to control the absorption rate of these drugs e.g. aluminium hydroxide slows
down the absorption of atropine sulphate to give a longer duration of action.
It is also used to maintain other drugs in blood at optimum concentrations
over a long period of time e.g. hyoscine butyl bromide.

CRITERIA FOR SELECTION OF ANTACIDS

1. Should not cause systemic alkalosis

2. Should not have constipation or laxative effect
3. Should exert its effect rapidly over a long period of time
4. Should buffer in a PH range of 4-6
5. Should not cause a large evolution of carbon dioxide

END OF SECOND YEAR WORK. WISH

YOU SUCCESS IN YOUR EXAMS

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