MISCELLANEOUS TEST: (by sadia iftikhar)(pharm.d 4th prof)oLoss on dryingoWeight per mloDetermination of water

LOSS ON DRYING(LOD)

REFERENCE:B.P 2013 : vol.V , appendix IX DUSP 30 NF25 : general test &

assay (physical test &

det. <731>) Eur. Ph: method 2.2.32

LOD(BP 2013)(eur.ph. 2.2.32)Lod is loss of mass expressed as

percent m/m.METHOD: .place the prescribed amount

of substance to be examined in a weighing bottle previously dried under specified condition.

.dry the substance to const. mass or for prescribed time by one of following methods:

a) In a “desiccators”: reagent : diphosphorus pentoxide pressure: atmospheric temp.: room temp.b) In a “vacuum”:Reagent: diphosphorus pentoxidePressure: 1.5 – 2.5 kPaTemp.: room temp.

c) Vacuum with sp. Temp. range:Reagent: diphosphorus pentoxidePressure: 1.5 – 2.5 kPaTemp: range given in monographd) In oven with sp. Temp. range:Apparatus : ovenTemp.: given in monograph

e) Under high vacuum:Reagent: diphosphorus pentoxidePressure: >0.1 kPaTemp.: given in monographNOTE:Where the drying temp. is indicated

by a single value rather than a range,drying is carried out at prescribed temp. ±2.

LOD(usp 30 NF25: <731>) This procedure determines the

amount of volatile matter of any kind.

But if the substance contain only water as a volatile matter then water determination <921> is suitable & is sp. In individual monograph

METHOD: .mix & accurately weigh the sample..take 1-2 g of sample or as directed in

individual monograph..if sample is in form of LARGE CRYSTALS then

reduce particle size to 2mm by crushing..dry the weighing bottle( glass stoppered,

shallow) for 30min. Under the same condition to be employed in determination.

.tare the weighing bottle.

.put sample in bottle, replace cover & accurately weigh the bottle & contents.

.distribute the sample by gentle sidewise shaking .

.sample should be distributed to a depth of 5mm , or if bulky material then <10mm.

.place the loaded weighing bottle in drying chamber, remove the stopper & also leave it in chamber.

.dry the sample at a temp sp. In indiviual monograph ( the temp should not >±2 of stated fig.).

.upon opening the chamber , close the bottle promptly , & allow it to come to room temp. in a desiccator before weighing .

SPECIFICATIONS:.w.r.t temp: if sample melts at a low temp.

than that sp. For LOD then maintain the bottle with its content for 1-2 hr at 5-10°C below the melting temp. then dry at sp. Temp.

. W.r.t sample: ..in case of CAPSULE, use a portion of mixed

content of not fewer than 4 capsules...in case of TABLETS, use powder from not

fewer than 4 tablets ground to a fine powder.

.W.r.t technique:When individual monograph directs that

LOD determine by THERMOGRAVIMETRIC analysis , a sensitive ELECTROBALANCE is to be used.

.w.r.t apparatus: ..when drying in VACUUM over a

DESICCANT is directed in individual monograph, a VACUUM DESICATOR or VACUUM DRYING PISTOL is used.

..where drying in CAPILLARY STOPPERED BOTTLE in vacuum is directed in individual monograph , use a bottle or tube fitted with a stopper having 225±25 micrometer dia capillary, & maintain heating chamber at a pressure of 5mmHg .

WEIGHT PER ML (DENSITY)REFERENCE:B.P 2013 : vol. v, appendix V G.

( by the name of wt. per ml)USP30 NF25: general test &

assay (phy. Test & det.

<616>).(by the name bulk density & tap density)

Eur. Ph : 2.2.5 ( by the name of “relative density”)

WEIGHT PER ML(BP 2013)“it is weight in g of 1ml of a liquid when

weighed in air at 20 degrees , unless otherwise sp. In monograph”.

METHOD: It is determined by: = weight in air (g)Weight of liquid that fill the pycnometer(ml).capacity of pycnometer is determined from

wt. in air (g), of the quantity of water required to fill pycnometer at that temp.

DENSITY;(P20)Determined by dividing the wt. in air of the quantity

of liquid being examined that fills pycnometer at 20 degree by weight in air of water required filling the pycnometer after making allowence for the thrust of air.

P20 = 998.2 (M1 + A) M2 + AM1= apparent mass (g) of sampleM2= apparent mass (g) of waterA = correction factor for thrust of air, 0.0012M2998.2= density of water at 20° in kgm^-3.

Relative density (Ph. Eur. method 2.2.5) The relative density of a substance is the ratio of the

mass of a certain volume of a substance at temperature t1 to the mass of an equal volume of water at temperature t2.

Unless otherwise indicated, the relative density d20^20 is used. Relative density is also commonly expressed as d4^20 . Density r20, defined as the mass of a unit volume of the substance at 20 °C may also be used, expressed in kilograms per cubic metre or grams per cubic centimetre (1 kg·m-3 = 10-3 g·cm-3). These quantities are related by the following equations where density is expressed in grams per cubic centimetre:

d4^20 = 0.998230 * d20^20Relative density or density are measured with

the precision to the number of decimals prescribed in the monograph using a density bottle (solids or liquids), a hydrostatic balance (solids), a hydrometer (liquids) or a digital density meter with an oscillating transducer (liquids and gases). When the determination is made by weighing, the buoyancy of air is disregarded, which may introduce an error of 1 unit in the 3rd decimal place. When using a density meter, the buoyancy of air has no influence.

Oscillating transducer density meter  The apparatus consists of:

 — a U-shaped tube, usually of borosilicate glass, which contains the liquid to be examined;

 — a magneto-electrical or piezo-electrical excitation system that causes the tube to oscillate as a cantilever oscillator at a characteristic frequency depending on the density of the liquid to be examined;

 — a means of measuring the oscillation period (T), which may be converted by the apparatus to give a direct reading of density, or used to calculate density using the constants A and B described below.

P = A * T^2 - B

Oscillating transducer meter

APPARENT DENSITY: The apparent density is calculated

from the following expression: apparent density = 997.2 × d20^20 where d20^20 is the relative density

of the substance being examined and 997.2 is the weight in air in kg of 1 cubic metre of water.

DETERMINATION OF WATERREFERENCE:B.P 2013: VOL.v , appendix IX CUsp 30 NF25 : phy. Test & deter.

<921>Eur. Ph.: 2.5.12(method 1), 2.2.13 (method 2), 2.5.32(method 3).

DETERMINATION OF WATER Method I (Ph. Eur. method 2.5.12) (bp 2013) The semi-micro determination of water is based upon the

quantitative reaction of water with sulfur dioxide and iodine in a suitable anhydrous medium in the presence of a base with sufficient buffering capacity.

Apparatus  The apparatus consists of a titration vessel with:

 — 2 identical platinum electrodes;  — tight inlets for introduction of solvent and titrant;  — an inlet for introduction of air via a desiccant;  — a sample inlet fitted with a stopper or, for liquids, a

septum. Inlet systems for introduction of dry nitrogen or for aspiration

of solvents may also be fitted.

The titration is carried out according to the instrument supplier's instructions. Care is taken throughout the determination to avoid exposure of reagents and solvents to atmospheric moisture. The end-point is determined using 2 identical indicator electrodes connected to an electrical source that maintains between the electrodes either a constant current or a constant voltage. Where direct titration is used (method A), addition of titrant causes either a decrease in voltage where constant current is maintained or an increase in current where constant voltage is maintained, until the end-point is reached. Instruments with automatic end-point detection are commonly used.

Standardisation  To the titration vessel, add methanol R, dried if necessary, or the solvent recommended by the supplier of the titrant. Where applicable for the apparatus used, eliminate residual water from the measurement cell or carry out a pre-titration. Introduce a suitable amount of water in an appropriate form (water R or a certified reference material) and carry out the titration, stirring for the necessary time. The water equivalent is not less than 80 per cent of that indicated by the supplier. Standardise the titrant before the first use and at suitable intervals thereafter.

Unless otherwise prescribed, use Method IA.

Method IA  Introduce into the titration vessel methanol R, or the solvent indicated in the monograph or recommended by the supplier of the titrant. Where applicable for the apparatus used, eliminate residual water from the measurement cell or carry out a pre-titration. Introduce the substance to be examined rapidly and carry out the titration, stirring for the necessary extraction time.

Method IB  Introduce into the titration vessel methanol R, or the solvent indicated in the monograph or recommended by the supplier of the titrant. Where applicable for the apparatus used, eliminate residual water from the measurement cell or carry out a pre-titration. Introduce the substance to be examined rapidly and in a suitable state of division. Add an accurately measured volume of the titrant, sufficient to give an excess of about 1 mL or the prescribed volume. Allow to stand protected from light for 1 min or the prescribed time, with stirring. Titrate the excess of reagent using methanol R or the prescribed solvent, containing an accurately known quantity of water.

Suitability  The accuracy of the determination with the chosen titrant must be verified for each substance to be examined. The following procedure, given as an example, is suitable for samples containing 2.5-25 mg of water.

The water content of the substance to be examined is determined using the reagent/solvent system chosen. Thereafter, sequential known amounts of water R are added in an appropriate form (at least 5 additions) and the cumulative water content determined after each addition

Method III (Coulometric titration) (Ph. Eur. method 2.5.32) (bp 2013) Principle  The coulometric titration of water is based upon

the quantitative reaction of water with sulfur dioxide and iodine in an anhydrous medium in the presence of a base with sufficient buffering capacity. In contrast to the volumetric method described under (2.5.12), iodine is produced electrochemically in the reaction cell by oxidation of iodide. The iodine produced at the anode reacts immediately with the water and the sulfur dioxide contained in the reaction cell. The amount of water in the substance is directly proportional to the quantity of electricity up until the titration end-point. When all of the water in the cell has been consumed, the end-point is reached and thus an excess of iodine appears. 1 mole of iodine corresponds to 1 mole of water, a quantity of electricity of 10.71 C corresponds to 1 mg of water.

Moisture is eliminated from the system by pre-electrolysis. Individual determinations can be carried out successively in the same reagent solution, under the following conditions:

 — each component of the test mixture is compatible with the other components,

 — no other reactions take place,

 — the volume and the water capacity of the electrolyte reagent are sufficient.

Coulometric titration is restricted to the quantitative determination of small

amounts of water, a range of 10 µg up to 10 mg of water is recommended. Accuracy and precision of the method are predominantly governed by the

extent to which atmospheric moisture is excluded from the system. Control of the system must be monitored by measuring the amount of baseline drift.

Apparatus  The apparatus consists of a reaction cell, electrodes and magnetic stirrer. The reaction cell consists of a large anode compartment and a smaller cathode compartment. Depending on the design of the electrode, both compartments can be separated by a diaphragm. Each compartment contains a platinum electrode. Liquid or solubilised samples are introduced through a septum, using a syringe. Alternatively, an evaporation technique may be used in which the sample is heated in a tube (oven) and the water is evaporated and carried into the cell by means of a stream of dry inert gas. The introduction of solid samples into the cell should in general be avoided. However, if it has to be done it is effected through a sealable port; appropriate precautions must be taken to avoid the introduction of moisture from air, such as working in a glove box in an atmosphere of dry inert gas. The analytical procedure is controlled by a suitable electronic device, which also displays the results.

Method  Fill the compartments of the reaction cell with electrolyte reagent for the micro determination of water R according to the manufacturer's instructions and perform the coulometric titration to a stable end-point. Introduce the prescribed amount of the substance to be examined into the reaction cell, stir for 30 s, if not otherwise indicated in the monograph, and titrate again to a stable end-point. In case an oven is used, the prescribed sample amount is introduced into the tube and heated. After evaporation of the water from the sample into the titration cell, the titration is started. Read the value from the instrument's output and calculate if necessary the percentage or amount of water that is present in the substance. When appropriate to the type of sample and the sample preparation, perform a blank titration.

Verification of the accuracy  Between two successive sample titrations, introduce an accurately weighed amount of water in the same order of magnitude as the amount of water in the sample, either as water R or in the form of standard

Method II Determination of water by distillation (Ph. Eur. method 2.2.13) The apparatus (see Figure 2.2.13.-1) consists

of a glass flask (A) connected by a tube (D) to a cylindrical tube (B) fitted with a graduated receiving tube (E) and reflux condenser (C). The receiving tube (E) is graduated in 0.1 mL. The source of heat is preferably an electric heater with rheostat control or an oil bath. The upper portion of the flask and the connecting tube may be insulated.

Method  Clean the receiving tube and the condenser of the apparatus, thoroughly rinse with water, and dry.

Introduce 200 mL of toluene R and about 2 mL of water R into the dry flask. Distil for 2 h, then allow to cool for about 30 min and read the water volume to the nearest 0.05 mL. Place in the flask a quantity of the substance, weighed with an accuracy of 1 per cent, expected to give about 2 mL to 3 mL of water. If the substance has a pasty consistency, weigh it in a boat of metal foil. Add a few pieces of porous material and heat the flask gently for 15 min. When the toluene begins to boil, distil at the rate of about two drops per second until most of the water has distilled over, then increase the rate of distillation to about four drops per second. When the water has all distilled over, rinse the inside of the condenser tube with toluene R. Continue the distillation for 5 min, remove the heat, allow the receiving tube to cool to room temperature and dislodge any droplets of water which adhere to the walls of the receiving tube. When the water and toluene have completely separated, read the volume of water and calculate the content present in the substance as millilitres per kilogram, using the formula:

= 1000(n2-n1) m m = the mass in grams of the substance to

be examined, N1= the number of millilitres of water

obtained in the first distillation, N2= the total number of millilitres of

water obtained in the 2 distillations.