Non-Aqueous Titrations

1
 Introduction
• Advances in the field of medicine has resulted in an overabundance of newer
complex organic medicinal compounds in the market.

• Evidently, these compounds posed two vital problems of quality control, both in
pure and dosage forms by virtue of their inherent characteristics, namely:

• (a) poor aqueous solubility, and

• (b) weak reactivity in aqueous medium.

• Initially, the above two problems were usually resolved in the following manner:

Example - 1 (Amine Salt):

• It is first changed to the water-insoluble free base,
• extracted with an appropriate organic solvent and treated with an excess volume
of standard acid;
• subsequently, the solvent was evaporated, and
• the remaining acid determined with a standard base. 2
Example - 2 (Sodium Salt): It is first acidified to release the water-insoluble
organic acid, extracted with a suitable organic solvent, the solvent was
removed and the residue was subsequently dried and weighed.

Example - 3 (Nitrogen containing compounds): They are estimated by micro

Kjeldahl’s Method.

• Nevertheless, such specific quantitative methods gave rise to certain serious

inconsistencies and drawbacks.
• In order to overcome these shortcomings the non-aqueous titrations were
introduced.

Different Definitions of Acids and Bases:

[1]. Acids and bases have long been defined as substances that, when
dissolved in water, furnish hydrogen and hydroxyl ions, respectively.
• This definition, introduced by Arrhenius, fails to recognize the fact that
properties characteristic of acids or bases may also be developed in other
solvents. 3
[2]. A more generalized definition is that of Brönsted, who defined an acid as a
proton donor, and a base as a proton acceptor.

• The concepts of the Lowry-Bronsted theory may explain the various reactions that
take place during many non-aqueous titrations.

• When an acid HA undergoes dissociation it gives rise to a proton and the conjugate
base A- of the acid:

[3]. Even broader is the definition of Lewis, who defined an acid as any material that
will accept an electron pair, a base as any material that will donate an electron pair,
and neutralization as the formation of a coordination bond between an acid and a
base.

Apparent Strength of an Acid or Base:

• The apparent strength of an acid or base is determined by the extent of its reaction
4
with a solvent.
Types of Solvents:
• Three types of solvents are discussed briefly here:
[1]. Protophillic Solvents: These are the solvents which have greater tendency
to accept protons. (Also called HBA i.e. hydrogen bond acceptor). Example of
protophilic solvents: Acetone, water, alcohol, liquid ammonia, etc.

• They are essentially basic in nature and normally react with acids to form
solvated protons as follows:

• A weakly basic solvent has less tendency than a strongly basic one to
accept a proton. Similarly a weak acid has less tendency to donate protons
than a strong acid.
• As a result, a strong acid such as perchloric acid exhibits more strongly
acidic properties than a weak acid such as acetic acid when dissolved in a
weakly basic solvent. 5
• On the other hand, all acids tend to become indistinguishable in strength
when dissolved in strongly basic solvents owing to the greater affinity of
strong bases for protons.

• This is called the leveling effect.

• Important Note: Strong bases are leveling solvents for acids, weak bases are
differentiating solvents for acids.

[2]. Protogenic Solvents: Protogenic solvents are acidic in nature and readily
donate a hydrogen ion (proton) in a chemical reaction.

Example of Protogenic solvents: Anhydrous acids such as hydrogen fluoride

(HF) and sulphuric acid (H2SO4) fall in this category.

Note: Because of their strength and ability to donate protons, they enhance
the strength of weak bases.
6
[3]. Amphiprotic Solvents: Amphiprotic solvents possess both protogenic and
protophillic properties in being able to donate protons and accept protons.

Examples: Weak organic acids (like acetic acid), water and alcohols etc. They
undergo dissociation to a very less extent.

Acetic acid is mostly employed as a solvent for the titration of basic substances
and its dissociation can be depicted as shown below:

• In the above instance acetic acid is behaving as an acid.

Perchloric acid is a very strong acid and when it is made to dissolve in acetic
acid, the acetic acid can behave as a base and forms an ‘onium ion’ after
combining with protons donated by the perchloric acid. Thus, we have:

7
• As the onium ion i.e. CH3COOH2+ ion can instantly donate its proton to a
base, therefore, a solution of perchloric acid in glacial acetic acid, behaves
as a strongly acidic solution.

• Pyridine, a weak base, when dissolved in acetic acid, the latter exerts its
levelling effect and subsequently increases the basic characteristics of the
pyridine.
• Therefore, it is practically feasible to titrate a solution of a weak base in
acetic acid against a mixture of perchloric acid in acetic acid. Thus, a sharp
end point is achieved which otherwise cannot be obtained when the
titration is performed in an aqueous medium.
• The various reactions with perchloric acid, acetic acid and pyridine are
summarized below:

8
Non-aqueous solvents used:
• Aprotic solvents are neutral, chemically inert substances such as benzene,
hydrocarbons, CCl4 and chloroform which have no tendency to yield and accept H+.

• They have a low dielectric constant, do not react with either acids or bases and
therefore do not favor ionization.

• The dielectric constant (symbol: ε) of a solvent is a measure of its bulk polarity. The
higher the dielectric constant of a solvent, the more polar it is.

• Example: The fact that picric acid gives a colorless solution in benzene which
becomes yellow on adding aniline shows that picric acid is not dissociated in
benzene solution and also that in the presence of the base aniline it functions as an
acid, the development of yellow color being due to formation of the picrate ion.

• Since dissociation is not an essential preliminary to neutralization, aprotic solvents

are often added to 'ionizing' solvents to depress solvolysis (which is comparable to
hydrolysis) of the neutralization product and so sharpen the endpoint.

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Leveling Effect or Solvent Leveling: 

• “It refers to the effect of solvent on the properties of acids and bases.”

• The strength of a strong acid is affected (leveled) by the basicity of the

solvent.

• Similarly the strength of a strong base is leveled by the acidity of the

solvent.

• Example: Acetic acid reacts incompletely with water to form a hydronium

ion and is therefore a weak acid. In contrast, it dissolves in a base such as
ethylenediamine and reacts so completely with the solvent that it behaves
as a strong acid.

• This so-called levelling effect is also observed for bases. In sulfuric acid
almost all bases appear to be of the same strength.
10
• Leveling Effect or Solvent Leveling can also be defined as “the tendency of
a solvent to make all Brønsted acids whose acidity exceeds a certain value
appear equally acidic.”

• Example: The apparent strength of a protonic acid is dependent on the

solvent in which the acid is dissolved.

• When all the acids in the acid chart which are stronger than H3O+ ion (i.e.,
the acids above H3O+ acids) are added to H2O, they donate as proton to H2O
to form H3O+ ion and appear to have equal strength.

• Since all these acids are levelled to the strength of H3O+ ion which is left in
solution and is common to all such solutions.

• This phenomenon i.e., the strength of all the acids becomes equal to that of
H3O+ ion is called leveling effect of the solvent, water, and here water is
called a leveling solvent for all these acids.
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Definition of Non-Aqueous Titrations:
• “Non-aqueous titrations are the titrations in which weakly acidic or basic
substances are carried out using non–aqueous solvents to get sharp end point.”
OR
• “Nonaqueous titration is the titration of substances dissolved in solvents other
than water.”

• It is the most common titrimetric procedure used in pharmacopoeial assays

and serves a double purpose: it is suitable for the titration of very weak acids
and very weak bases, and it provides a solvent in which organic compounds are
soluble.

• Precautions: Moisture and carbon dioxide are to be avoided in non– aqueous

methods. The moisture content in non–aqueous titrations should not be more
than 0.05%.

• The most commonly used procedure is the titration of organic bases with
perchloric acid in anhydrous acetic acid. These assays sometimes take some
perfecting in terms of being able to judge the endpoint precisely.
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Theory of Non-Aqueous Titrations:

• Acid-base reactions: The theory is that water behaves as both a weak acid

and a weak base; thus, in an aqueous environment, it can compete
effectively with very weak acids and bases with regard to proton donation
and acceptance.

• The reaction H2O + H+ ⇌ H3O+ competes with RNH2 + H+ ⇌ RNH3+ or

H2O + B ⇌ OH− + BH+ competes with ROH + B ⇌ RO− + BH+

• The effect of this is that the inflection in the titration curves for very weak

acids and very weak bases is small, because they approach the pH limits in
water of 14 or 0 respectively, thus making endpoint detection relatively
more difficult.

• A general rule is that bases with pKa < 7 or acids with pKa > 7 cannot be
determined accurately in aqueous solution. (Hint: For acids, the smaller
the pKa, the more acidic the substance is (the more easily a proton is lost,
13
thus the lower the pH).
• Substances which are either too weakly basic or too weakly acidic and
dont give sharp endpoints in aqueous solution can often be titrated in
nonaqueous solvents.

• The reactions which occur during many nonaqueous titrations can be

explained by means of the concepts of the Brønsted-Lowry theory.

• According to this theory an acid is a proton donor, i.e. a substance which

tends to dissociate to yield a proton, and a base is proton acceptor, i.e. a
substance which tends to combine with a proton.

• When an acid HB dissociates it yields a proton together with the conjugate

base B of the acid:
HB (acid) ⇌ H+ (proton) + B− (conjugate base)

• Alternatively, the base B will combine with a proton to yield the conjugate
acid HB of the base B, for every base has its conjugate acid and, every acid
has its conjugate base. 14
• It follows from these definitions that an acid may be either:
1. an electrically neutral molecule, e.g. HCl, or
2. a positively charged cation, e.g. C6H5NH3+.

• A base may be either:

1. an electrically neutral molecule, e.g. C6H5NH2, or
2. an anion, e.g. Cl−.

• Substances which are potentially acidic can function as acids only in the
presence of a base to which they can donate a proton. Conversely basic
properties do not become apparent unless an acid also is present.

Organic Solvents:
• Various organic solvents may be used to replace water since they compete
less effectively with the analyte for proton donation or acceptance.

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End-Point Determination in Nonaqueous Titration:
• The end-point may be determined visually by colour change or
preferentially by potentiometry.

[1]. Visual indicators: The following indicators are in common use:

Important Note: It should be recognized that certain indicators in common use

(crystal violet, for example) undergo a series of colour changes and, in
establishing a nonaqueous titration method for a particular use, care should
be taken to ensure that the colour change specified as the end-point of the
titration corresponds to the maximum value of dE/dV (where E is the
electromotive force and V the volume of titrant) in a potentiometric titration of
the substance under consideration. 16
[2]. Potentiometric Method:
• The end point of most titrations is detected by the use of visual indicator but the
method can be inaccurate in very dilute or colored solutions.

• However, under the same conditions, a potentiometric method for the detection of the
equivalence point can yield accurate results without difficulty.

• The electrical apparatus required consists of a potentiometer or pH meter with a

suitable indicator and reference electrode. The other apparatus consists of a burette,
beaker and stirrer.

• The actual potential of the “reference electrode” need not be known accurately for
most purposes and usually any electrode may be used provided its potential remains
constant throughout the titration.

• The “indicator electrode” must be suitable for the particular type of titration (i.e. a
glass electrode for acid-base reactions and a platinum electrode for redox titrations),
and should reach equilibrium rapidly.

• The electrodes are immersed in the solution to be titrated and the potential difference
17
between the electrodes is measured.
• Measured volumes of titrant are added, with thorough (magnetic) stirring,
and the corresponding values of emf (electromotive force) or pH recorded.

• Small increments in volume should be added near the equivalence point

which is found graphically by noting the burette reading corresponding to
the maximum change of emf or pH per unit change of volume.

• When the slope of the curve is more gradual it is not always easy to locate
the equivalent point by this method.

• However, if small increments (0.1 cm³ or less) of titrant are added near the
end point of the titration and a curve of change of emf or pH per unit
volume against volume of titrant is plotted, a differential curve is obtained
in which the equivalence point is indicated by a peak.

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Methodology of Non-Aqueous Titrations:
• For non-aqueous titrations, the following four steps are usually taken into
consideration, namely:

(i) Preparation of 0.1 N Perchloric acid,

(ii) Standardization of 0.1 N Perchloric Acid,
(iii) Choice of Indicators, and
(iv) Effect of Temperature on Assays.

[1]. Preparation of 0.1 N Perchloric Acid:

• Materials Required: 8.5 ml of perchloric acid (70.0 to 72.0%); 1 Litre of glacial
acetic acid; 30 ml of acetic anhydride.

• Perchloric acid has a molecular weight of 100.46 and 1 L of 0.1 N solution

shall contain 1 /10th the equivalent weight or 10.046 g.

• To prepare 1 L of standard perchloric acid solution, it requires 8.5 ml (sp. gr.

1.6) volume and a purity of 72% which will calculate out as 9.792 g of HClO 4. 19
Procedure: Gradually mix 8.5 ml of perchloric acid to 900 ml of glacial acetic
acid with vigorous and continuous stirring. Now add 30 ml acetic anhydride
and make up the volume to 1 litre with glacial acetic acid and allow to stand for
24 hours before use.

Important Note: The acetic anhydride reacts with the water (approx. 30%) in
perchloric acid and some traces in glacial acetic acid thereby making the
resulting mixture practically anhydrous. Thus, we have :

Precautions: The following precautions must be observed :

(a). Perchloric acid is usually available as a 70 to 72% mixture with water (sp.
gr. 1.6). It usually undergoes a spontaneous explosive decomposition and,
therefore, it is available always in the form of a solution.

20
(b). Conversion of acetic anhydride to acetic acid requires 40-45 minutes for its
completion. It being an exothermic reaction, the solution must be allowed to
cool to room temperature before adding glacial acetic acid to volume.

(c). Avoid adding an excess of acetic anhydride especially when primary and
secondary amines are to be assayed, because these may be converted rapidly to
their corresponding acetylated non-basic products:

(d). Perchloric acid is not only a powerful oxidising agent but also a strong acid.
Hence, it must be handled very carefully.

[2]. Standardization of 0.1 N Perchloric Acid:

• In usual practice, potassium hydrogen phthalate (or potassium biphthalate) is
employed as a standardizing agent for acetous perchloric acid.

• Note: Alkaline earth (e.g., Mg, Ca, Ba) and alkali (e.g., Na, K, Rb) salts of
21
organic acids behave as bases in acetic acid solution.
• The reaction may be expressed as follows:

Procedure:
• Weigh accurately about 0.5 g of potassium hydrogen phthalate in a 100 ml
conical flask.

• Add 25 ml of glacial acetic acid and attach a reflux condenser fitted with a silica-
gel drying tube. Warm until the salt gets dissolved completely.

• Cool and titrate with 0.1 N perchloric acid by making use of either of the
following two indicators: 22
(a). Acetous crystal violet-2 drops, end point Blue to Blue-Green (0.5% w/v)
(b). Acetous oracet blue B-2 drops, end point Blue to Pink.

[3]. Choice of Indicators:

• A number of indicators stated below are commonly used in non-aqueous
titrations. It is, however, necessary to mention here that the same indicator
must be used throughout for carrying out the standardization, titration and
neutralization of mercuric acetate solution.

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[4]. Effect of Temperature on Assays:
• Generally, most non-aqueous solvents possess greater coeffcients of
expansion as compared to water, which is why small differences in
temperature may afford significant and appreciable errors that can be
eliminated by the application of appropriate correction factors.

• Hence, it is always advisable to carry out standardization and titration

preferably at the same temperature.

• In a situation where these temperature parameters cannot be achieved, the

volume of titrant may be corrected by the application of the following formula:

Vc = V [1 + 0.001 (t1 + t2)]

where,
Vc = Corrected volume of titrant,
V = Volume of titrant measured,
t1 = Temperature at which titrant was standardized, and
t2 = Temperature at which titration was performed. 24
 Assay by Non-Aqueous Titrations
• Assays of various pharmaceutical substances either in pure form or in
dosage form may be assayed successfully by non-aqueous titrations.

• For the sake of convenience, these typical titrations can be categorized into
two broad groups, namely:

1. Acidimetry in Non-aqueous Titrations: It can be further sub-divided into

two types, namely: (i) Titration of primary, secondary and tertiary amines,
and (ii) Titration of halogen acid salts of bases.

2. Alkalimetry in Non-aqueous Titrations i.e., titration of acidic substances.

[A]. Acidimetry in Non-Aqueous Titrations:

• In order to perform feasible titrations of weak bases, the solvent system
should be selected specifically in such a fashion so as to eliminate as far as
possible the competing reaction of water for the proton besides enhancing
the strength of the basic species. 25
[1]. Titration of Amines:
Example of Methlyldopa Assay: In general, the reaction taking place between
a primary amine and perchloric acid may be expressed as follows:

• The specific reaction between methyldopa and perchloric acid is expressed

by the following equation:

26
• Materials Required: Methyldopa 0.2 g; anhydrous formic acid: 15 ml; glacial
acetic acid: 30 ml; dioxane: 30 ml; 0.1 N perchloric acid and crystal violet
solution.
• Procedure: Weigh accurately about 0.2 g methyldopa and dissolve it in 15 ml
of anhydrous formic acid, 30 ml of glacial acetic acid and 30 ml of dioxane.
Add 0.1 ml of crystal violet solution and titrate with 0.1 N perchloric acid.
Perform a blank determination and make any necessary correction.

• Each ml of 0.1 N perchloric acid is equivalent to 0.02112 g of C10H13NO4

(methyldopa).

• Calculations: The percentage of methyldopa present in the sample is given

by:

• Note: When acetic anhydride is the medium (for halide salts of weak bases
and quaternary ammonium compounds), a volumetric solution of perchloric
acid in glacial acetic acid may be used as the titrant.
27
Potentiometric Titrations:
• These non-aqueous titrations may also be carried out with the help of
potentiometric titrations.

• It is always preferred to first ascertain the equivalence point of a given

neutralization reaction potentiometrically (i.e., an instrumental method of
analysis); and secondly, by selecting an appropriate indicator that will
ensure the sharpest colour change for the least increment of volume of
titrant added near the equivalence point.

• In actual practice, however, there are quite a number of non-aqueous

titrations of pharmaceutical substances either in pure or in dosage forms
that can be successfully performed potentiometrically.

[2]. Titration of Halogen Acid Salts of Bases:

• In general, the halide ions, namely: chloride, bromide and iodide are very
weakly basic in character so they cannot react quantitatively with acetous
perchloric acid. 28
• In order to overcome this problem, mercuric acetate is usually added to a
halide salt thereby causing the replacement of halide ion by an equivalent
amount of acetate ion, which serves as a strong base in acetic acid as shown
below:

Note: Mercuric acetate remains undissociated in acetic acid solution.

Example of Amitriptyline Hydrochloride Assay:

• Materials Required: Amitriptyline hydrochloride: 1.0 g; mercuric acetate;
crystal violet; 0.1 N perchloric acid; glacial acetic acid.

• Procedure: Weigh accurately about 1.0 g and dissolve in 50 ml of glacial acetic

acid, warming slightly, if necessary, to affect the solution.
• Cool, add 10 ml of mercuric acetate solution, two drops of crystal violet
29
solution and titrate with 0.1 N perchloric acid to a green end-point.
• Perform a blank determination and make any necessary correction. Each ml
of 0.1 N perchloric acid is equivalent to 0.03139 g of C20H23N. HCl
(amitriptyline hydrochloride).

• Equations:

[B]. Alkalimetry in Non-Aqueous Titrations:

• Many of weakly acidic pharmaceutical substances may be titrated
effectively by making use of a suitable non-aqueous solvent with a sharp
end-point.
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• The wide spectrum of such organic compounds include: anhydrides, acids,
amino acids, acid halides, enols (viz., barbiturates), xanthines,
sulphonamides, phenols, imides and lastly the organic salts of inorganic
acids.
• However, a weak inorganic acid e.g., boric acid, can be estimated conveniently
employing ethylenediamine as the non-aqueous solvent.

Basic Titrants/Solvents:
[1]. Preparation of 0.1 N Potassium Methoxide in Toluene-Methanol:
• Materials Required: Absolute methanol: 40 ml; dry toluene: 50 ml; potassium
metal: 4 g.

• Procedure: Add into a dry flask, a mixture of methanol (40 ml) and dry toluene
(50 ml) and cover it loosely.
• Carefully add freshly cut pieces of potassium metal to the above mixture
gradually with constant shaking.

• After complete dissolution of potassium metal, add enough absolute methanol

31
to yield a clear solution.
• Note: Toluene 50 ml is added with constant shaking until the mixture turns
hazy in appearance.

• The process is repeated by the alternate addition of methanol and toluene

until 1 litre of solution is obtained, taking care to add a minimum volume of
methanol to give a visible clear solution.

[2]. Preparation of 0.1 N Sodium Methoxide:

• It is prepared exactly in a similar manner as for 0.1 N Potassium Methoxide,
using 2.3 g of freshly-cut sodium in place of potassium.

[3]. Preparation of 0.1 N Lithium Methoxide:

• It is prepared as for 0.1 N Potassium Methoxide, but using 0.7 g of lithium in
place of potassium.

Standardization of 0.1 N Methoxide Solution:

• Materials Required: Dimethylformamide (DMF): 10 ml; thymol blue (0.3% in
MeOH); 0.1 N lithium methoxide in toluene-methanol; benzoic acid: 0.6 g.
32
• Procedure: The apparatus shown in Figure below, is employed for the
standardization of 0.1 N methoxide solution.

• Transfer 10 ml of DMF in a conical

flask and add to it 3 to 4 drops of
thymol blue and first neutralize the
acidic impurities present in DMF by
titrating with 0.1 N lithium
methoxide in toluene-methanol.

• Quickly introduce 0.06 g of benzoic

acid and titrate immediately with
methoxide in toluene-methanol.

• Caution: Care must be taken to

avoid contamination of neutralized
liquid with atmospheric carbon
dioxide.

33
• Equations: The various equations involved in the above operations are
summarized as stated below:

• Interaction between sodium metal and methanol is an exothermic

reaction and hence, special care must be taken while adding the metal into
the dry solvent in small lots at intervals with adequate cooling so as to
keep the reaction well under control.
• Important Precaution: The clear solution of sodium methoxide must be
kept away from moisture and atmospheric CO2 as far as possible so as to
avoid the following two chemical reactions that might ultimately result into
the formation of turbidity.

34
• Step 1: It shows the solution of benzoic acid (primary standard) in DMF,
• Step 2: It depicts ionization of sodium methoxide,
• Step 3: It illustrates the interaction between the solvated proton and the
methylated ion.

• In summing up, the net reaction in the process of standardization has been
expressed.
• The interaction between the water in the solvent (DMF) and the titrant is
equivalent to the volume of sodium methoxide consumed by DMF or may be
considered as a blank determination.

Example of Ethosuximide Assay:

• Materials Required: Ethosuximide: 0.2 g; dimethylformamide: 50 ml; azo-
violet (0.1% w/v in DMF): 2 drops; sodium methoxide 0.1 N.

• Procedure: Weigh accurately about 0.2 g ethosuximide, dissolve in 50 ml of

dimethylformamide (DMF), add 2 drops of azo-violet solution and tirate with
0.1 N sodium methoxide to a deep blue end point, taking precautions to
35
prevent absorption of atmospheric carbon dioxide.
• Perform a blank determination and make any necessary correction. Each ml
of 0.1 N sodium methoxide is equivalent to 0.01412 g of C 7H11NO2
(ethosuximide).

• Equations:

[4]. Tetrabutylammonium Hydroxide:

• The alkalimetry in non-aqueous titrations may also be carried out efficiently
by using tetrabutylammonium hydroxide along with an appropriate
indicatior.
36
Summary of Titrants Used in Non Aqueous Alkalimetric Titrations:

1. In order of decreasing strength, strong bases of value for non-aqueous

titrations are potassium methoxide, sodium methoxide, lithium methoxide
and tetrabutylammonium hydroxide.

2. When ethanol is used as the medium for halide salts of weak bases the
titrant is a volumetric solution of sodium hydroxide.

3. In the titration of an acidic compound a volumetric solution of lithium

methoxide in a methanol-toluene solvent is often used. For many
applications it is convenient to use a solution of tetrabutylammonium
hydroxide in toluene.

• Precaution: Because of interference by carbon dioxide, solvents for acidic

compounds must be protected from excessive exposure to the atmosphere
by a suitable cover or by an inert atmosphere during the titration.
37
Advantages/Applications of Non-aqueous Titrations:
Non-aqueous titrations have the following advantages, namely:

[1]. Elimination of poor solubility of substances: Organic acids and bases that
are insoluble in water are soluble in nonaqueous solvent.

[2]. Enhancement of reactivity of substances: Non-aqueous solvents are

useful for the titration of very weak acids or bases that cannot be titrated in
water.

Many water-insoluble compounds acquire enhanced acidic or basic properties

when dissolved in organic solvents. Thus the choice of the appropriate medium
and titrant permits the determination of a variety of such materials by non-
aqueous titration.

[3]. Selective titration by using suitable solvent and titrant of acidic/basic

components of physiologically active moiety of a salt.
38
[4]. Maintenance of speed, precision, accuracy and simplicity.

[5]. Weak bases which have Kb values less than 10–6 can be titrated
satisfactorily by non-aqueous titrations. The reason being that in aqueous
medium and at higher Kb values (> 10–6) the solvent water competes
progressively with the basic species in solution for the proton of the solvent.

[6]. The Karl Fischer titration for water content is another nonaqueous
titration, usually done in methanol or sometimes in ethanol. Since water is the
analyte in this method, it cannot also be used as the solvent.

Types of Compounds Titrated by Non-Aqueous Titrations:

[A]. The types of compounds, in a non-aqueous medium, that may be titrated

as acids, usually by lithium methoxide or tetrabutyl ammonium hydroxide,
include acid halides, acid anhydrides, carboxylic acids, amino acids, enols
such as barbiturates and xanthines, imides, phenols, pyrroles and
sulfonamides. 39
[B]. The types of compounds, in a non-aqueous medium, that may be titrated
as bases by perchloric acid, include amines, nitrogen-containing heterocyclic
compounds, quarternary ammonium compounds, alkali salts of organic acids,
alkali salts of inorganic acids and some salts of amines.

[C]. Many halide salts of weak bases and some quaternary ammonium
compounds may be directly titrated in acetic anhydride using, preferably,
potentiometric end-point detection or an indicator such as malachite green or
crystal violet.
• In short, it is possible to titrate mixtures of two or three components
selectively with a single titration by wisdom of the right choice of solvent for
the non-aqueous titrations.

• References:
1. Pharmaceutical Drug Analysis (2nd edition) by Ashutosh Kar.
2. Internet 40