PHARMACEUTICAL QUALITY CONTROL; micellaneous tests

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PHARMACEUTICAL QUALITY CONTROL:

PHARMACEUTICAL QUALITY CONTROL DR. NAUREEN SHEHZADI M.PHIL. (PHARMACEUTICAL CHEMISTRY) UNIVERSITY OF THE PUNJAB, LAHORE, PAKISTAN

MICELLANEOUS DETERMINATIONS AND TESTS:

MICELLANEOUS DETERMINATIONS AND TESTS Determination of; Weight/ml Loss on Drying Water/Moisture content Ash contents Alkalinity of Glass Toxicity tests Identification tests Evaluation of Ointments

WEIGHT PER ML:

WEIGHT PER ML

Definition :

Definition The weight per milliliter of a liquid is the weight, in g, of 1 mL of a liquid when weighed in air at 20°, unless otherwise specified in the monograph. British pharmacopoeia, 2012 online (Appendix V G.) Simply, it may be defined as the weight, expressed in grams, of 1 mL of a liquid when weighed in air at the specific temperature.

Why determined?:

W hy determined? Batch to batch thickness maintenance (variables are water, actives, excipients, impurities etc.) of liquid preparations such as suspensions, syrups and semi-liquid preparations e.g. ointments. Preparations/formulations for which assays are not possible i.e. formulation or preparation is a complex mixture e.g. tea

Formulations exposed to weight/ml test:

Formulations exposed to weight/ml test Complex mixtures (containing more than 1 actives) Extracts Tinctures Oral solutions Oral suspension Syrups Galanicals The quantity of the oral solution or suspension taken for assay purposes is weighed accurately and the weight per ml determined in order to calculate the content as weight in volume (g per ml). (WHO Pharmacopeia Library)

Procedure :

Procedure Take a clean, dry pycnometer. Calibrate the pycnometer by filling it in a freshly boiled and cooled water at 20 °C and weighing the contents. Calculate the capacity of pycnometer by assuming that the weight of 1ml of water at 20 °C when weighed in air of density 0.0012g/ml is 0.997. Adjust the temperature of the substance under investigation to 20 °C and fill the pycnometer with it in such a way that no bubble formation takes place. Adjust the temperature of filled pycnometer to 20°C, remove the excess of liquid and weigh. Subtract the tare weight of pycnometer from the filled weight of pycnometer. Calculate the weight per milliliter by dividing the weight (in g) of the quantity of liquid that fills a pycnometer at the specified temperature by the capacity, expressed in ml, of the pycnometer at the same temperature.

Calculations :

Calculations   Weight of pycnometer = W1 A grams Weight of pycnometer + Liquid sample = W2 B grams Weight of liquid sample = W3 C = B – A Capacity of pycnometer = V Weight/ml E = C/V

British pharmacopoeia table:

British pharmacopoeia table The weight of a liter of water at specified temperatures when weighed against brass weights in air of density 0.0012 g per mL is given in the following table. Ordinary deviations in the density of air from the above value, here taken as the mean, do not affect the result of a determination in the significant figures prescribed for Pharmacopoeial substances. Temperature Weight of a liter of water °C G 20 997.18 25 996.02 30 994.62

Experimental (Lab part):

Experimental (Lab part) Calculate in lab, the weight per ml of; Propylene glycol Glycerin Amoxicillin suspension Tixylix syrup Panadol syrup Palmonal syrup Betnovate ointment

LOSS ON DRYING:

LOSS ON DRYING

Definition :

Definition Loss on drying is the loss of mass expressed as per cent m/m. British pharmacopoeia, 2012 online (Appendix IX D.) This test determines the amount of volatile matter of any kind (volatile compounds; not necessarily water) that is driven of under specified conditions.

Difference with moisture content:

Difference with moisture content The term Loss on drying is used in those cases where the loss sustained on heating may be not entirely water; volatile compound . The term moisture content is used in those cases where the loss sustained on heating is entirely water . Where the water of hydration or adsorbed water of a Pharmacopoeial article is determined by the titrimetric method, the test is generally given under the heading Water. Monograph limits expressed as a percentage are figured on a weight/weight basis unless otherwise specified . Where the determination is made by drying under specified conditions, the test is generally given under the heading Loss on drying. However, Loss on drying is most often given as the heading where the loss in weight is known to represent residual volatile constituents , including organic solvents as well as water . USP30-NF25

Why determined?:

W hy determined? Many Pharmacopoeial articles either are hydrates or contain water in adsorbed form. Also, some of the drug matters do contain volatile or organic components. The determination of such content is important in demonstrating compliance with the Pharmacopoeial standards.

Formulations exposed to test:

Formulations exposed to test Extracts Tinctures Powders containing volatile components other than water Capsules Tablets

Procedure:

Procedure Unless otherwise stated in an individual monograph, conduct the determination on 1-2g of substance. Accurately weigh and mix the substance to be tested and if and the substance is in the form of large particles, reduce the particle size to about 2 mm by quickly crushing before weighing out. Tare a glass stoppered, shallow weighing bottle that has been dried for 30 minutes under the same conditions to be employed in determination and cooled to room temperature in a desiccator. Put the test specimen in the bottle, replace the cover and accurately weigh the bottle and contents.

Conti….:

Conti…. By gentle, sidewise shaking, distribute the test specimen as evenly as practicable to a depth of about 5 mm generally and not more than 10mm in the case of bulky material. Place the loaded bottle in the drying chamber, removing the stopper and leaving it also in the chamber. Dry the test specimen at the temperature and for the time specified in the monograph (drying is carried out at the prescribed temperature ± 2 ° C). Upon opening the chamber, close the bottle promptly, and allow it to come to room temperature in a desiccator before weighing. (USP34, <731 >)

Calculations :

Calculations Weight of bottle and contents before drying = W1 A grams Weight of bottle and contents after drying = W2 B grams Loss on drying (%) = W3 C = (A – B)* 100

Note :

Note If the substance melts at a lower temperature than that specified for the determination of Loss on drying, maintain the bottle with its contents for 1 to 2 hours at a temperature 5 to 10 ° below the melting temperature, then dry at the specified temperature . Where the specimen under test is Capsules, use a portion of the mixed contents of not fewer than 4 capsules. Where the specimen under test is Tablets, use powder from not fewer than 4 tablets ground to a fine powder.

PowerPoint Presentation:

Where the individual monograph directs that loss on drying be determined by thermogravimetric analysis , a sensitive electro balance is to be used.

PowerPoint Presentation:

Where drying in vacuum over a desiccant is directed in the individual monograph, a vacuum desiccator or a vacuum drying pistol, or other suitable vacuum drying apparatus, is to be used .

PowerPoint Presentation:

Where drying in a desiccator is specified , exercise particular care to ensure that the desiccant is kept fully effective by frequent replacement.

PowerPoint Presentation:

Where drying in a capillary-stoppered bottle in vacuum is directed in the individual monograph, use a bottle or tube fitted with a stopper having a 225 ± 25μm diameter capillary, and maintain the heating chamber at a pressure of 5 mm or less of mercury. At the end of the heating period, admit dry air to the heating chamber, remove the bottle, and with the capillary stopper still in place allow it to cool in a desiccator before weighing.

Experimental (Lab part):

Experimental (Lab part) Determine in lab, the loss on drying of; Fennel powder Coriander powder Ginger powder Thyme powder Iodine tincture

MOISTURE CONTENT:

MOISTURE CONTENT

Definition :

Definition This test determines the amount of water (as the volatile matter) that is driven of under specified conditions. British pharmacopoeia, 2012 online (Appendix V G.) .

Importance of determination :

Importance of determination Many Pharmacopoeial articles either are hydrates or contain water in adsorbed form. As a result, the determination of the water content is important in demonstrating compliance with the Pharmacopoeial standards . Presence of water beyond the acceptance limits interferes with quality of the drug since its presence may affect; 1- Drug stability 2- Microbial degradation of drug

Formulations exposed to the test:

Formulations exposed to the test When water is the only volatile component, this test is usually employed Water extracts Tinctures Powders Granules Tablets Capsules

Procedure :

Procedure

Titrimetric method:

Titrimetric method It is also known as Karl Fischer method. It is a method of water determination in the technical products ( oil, plastics and gases), in cosmetic products, in pharmaceutical products and in food industry. It is a standard technique for low moisture containing products KARL FISCHER TITRATION METHODS The test specimen may be titrated with the reagent directly or analysis may be carried out by a residual titration procedure .

Volumetric titration:

Volumetric titration BASIC PRINCIPLE: The titrimetric determination of water is based on quantitative reaction of water with anhydrous solution of sulfur dioxide and iodine in the presence of methanol and pyridine. Range of application 0.1 % - 100 % depends on sample size. Step 1: H 2 O + I 2 + SO 2 + 3C 5 H 5 N 2 [C 5 H 5 N+H]I + C 5 H 5 NSO 3 Step 2: C 5 H 5 NSO 3 + CH 3 OH  [ C 5 H 5 N+H]O.SO 2. OCH 3 Dissolve Iodine in a mixture of pyridine, Methanol and SO 2.

PowerPoint Presentation:

DIRECT TITRATION Fill titration vessel with solvent Pre-titration with KF reagent Add the sample Titrate with KF reagent Concentration of KF Reagent = mg H 2 O /ml of Reagent % H2O = [Concentration x ml Reagent/mg of Sample] x 100 RESIDUAL TITRATION In the residual titration, excess Reagent is added to the test specimen, sufficient time is allowed for the reaction to reach completion, and the unconsumed Reagent is titrated with a standard solution of water in a solvent such as methanol.

Coulometric titration:

Coulometric titration The main compartment of the titration cell contains ; The anode solution (A solution containing alcohol, a base, SO2 and I2). The analyte Cathode immersed in the anode solution T he two compartments (anode and cathode) are separated by an ion-permeable membrane. The Pt anode generates I2 when current is provided through the electric circuit. One mole of I2 is consumed for each mole of H2O. In other words, 2 moles of electrons are consumed per mole of water.

PowerPoint Presentation:

H + H I I - - - + - The end point is detected most commonly by immersing a second pair of Pt electrodes in the anode solution. The detector circuit maintains a constant current between the two detector electrodes during titration. Prior to the equivalence point, the solution contains I- but little I2. At the equivalence point, excess I2 appears and an abrupt voltage drop marks the end point. The amount of current needed to generate I2 and reach the end point can then be used to calculate the amount of water in the original sample. Coulometry is best suited for determination of water content in the range of 1 ppm to 5ppm.

Azeotropic method:

Azeotropic method It is useful for the detection of the water in oily and semi-solid preparations. As the test substance is heated, any water present in the sample vaporizes . The water vapors are then condensed and collected in a graduated collection tube, such that the volume of water produced by distillation can be measured as a function of the total volume of oil used .

Gravimetric method:

Gravimetric method Unless otherwise prescribed in the original monograph, weigh accurately 2 g of the powder material in a tarred silica crucible. Dry the powder in an oven at 105 ° C for 30 min and cool it at room temperature in desiccators until constant weight is obtained. Calculate the moisture contents difference in the weight of powdered drug before and after drying. The results are expressed as a percentage of dry powdered drug In case of articles of botanical origin, Place about 10g of the drug, prepared as directed (Methods of Analysis, Under Articles of Botanical Origin, 561) and accurately weighed , in a tared evaporating dish. Dry at 105 ° for 5hours , and weigh. Continue the drying and weighing at 1 hour intervals until the difference between two successive weighing corresponds to not more than 0.25%. (USP34 – NF29, First supplement, <921 >)

Calculations :

Calculations Weight of bottle and contents before drying = W1 A grams Weight of bottle and contents after drying = W2 B grams Loss on drying (%) = W3 C = (A – B)* 100

Experimental (Lab part):

Experimental (Lab part) Calculate in lab, the moisture content of following by gravimetric method; Soil Ibuprofen tablet Paracetamol tablet Sodium bicarbonate

ASH CONTENT:

ASH CONTENT

Definition :

Definition Ash is the name given to all non-aqueous residue that remains after a sample is burned, which consists mostly of metal oxides .

Importance of determination :

Importance of determination Determination of inorganic impurities in organic substances.

Formulations exposed to test:

Formulations exposed to test Herbal preparations (powders)

Procedure :

Procedure

1- Total ash:

1- Total ash Unless otherwise specified in monograph, incinerate about 2-3grams of the ground drug on a tared platinum or silica dish at temperature not exceeding 450 °C until free from carbon. Cool the contents and weigh. Calculate the ash using following formula; If carbon free ash cannot be determined as prescribed earlier, then; 1- Exhaust the charred mass with hot water 2- Collect the residue on ash-less filter paper 3- Incinerate the residue and filter paper 4- A dd the filtrate, evaporate to dryness 5- Ignite to constant weight at temperature not exceeding 450°C  

2- Sulphated ash:

2- Sulphated ash Unless otherwise s tated In individual monograph, place 2-3gram sample substance in a platinum dish. Moisten the drug with sulphuric acid (1760g/L), heat gently to remove excess of the acid and ignite at about 800°C until all the black particles have disappeared. Again moisten with sulphuric acid and ignite at 800°C. Add a small amount of ammonium carbonate and ignite to constant weight. Calculate the percentage of ash with reference to air-dried drug  

3- Water soluble ash:

3- Water soluble ash Incinerate about 2-3grams of the ground drug on a tared platinum or silica dish at temperature not exceeding 450°C until free from carbon. Boil the ash for 5minutes with 25ml of water. Collect the insoluble matter in a Gooch crucible or ash-less filter paper. Wash with hot water. Ignite the contents for 15minutes at a temperature not exceeding 450°C. Cool and weigh. Calculate the percentage of ash with reference to air-dried drug  

4- Acid insoluble ash:

4- Acid insoluble ash Incinerate about 2-3grams of the ground drug on a tared platinum or silica dish at temperature not exceeding 450°C until free from carbon. Boil the ash for 5minutes with 25ml of 2M HCl. Collect the insoluble matter in a Gooch crucible or ash-less filter paper. Wash with hot water. Ignite the contents for 15minutes at a temperature not exceeding 450°C to a constant weight. Cool and weigh. Calculate the percentage of ash with reference to air-dried drug  

ALKALINITY OF THE GLASS:

ALKALINITY OF THE GLASS

Definition :

Definition A glass is a super cooled liquid. Glass containers are most commonly used primary packaging materials.

Types of glass :

Types of glass TYPE 1: Highly resistant borosilicate glass TYPE 2: Treated soda-lime glass TYPE 3: Regular soda-lime glass TYPE 4: General purpose soda-lime glass . Type 1, 2, 3 are intended for parenteral products and type 4 is used for non-parenteral products (oral or topical used preparations)

Composition and alkalinity of glass:

Composition and alkalinity of glass It is composed of a network of silicon and oxygen atom. Silica (the chemical compound SiO 2 ) is a common fundamental constituent of glass. Other ingredients incorporated in the glass are sodium carbonate (Na 2 CO 3 , "soda"), which lowers the glass transition temperature, lime (CaO), some magnesium oxide (MgO) and aluminum oxide (Al 2 O 3 ) are added to provide for a better chemical durability. The resulting glass contains about 70 to 74% silica by weight and is called a soda-lime glass . Soda-lime glasses account for about 90% of manufactured glass . Borosilicate glasses (e.g. Pyrex, 81% silica) have as main constituents silica and boron oxide.

Importance of determination :

Importance of determination Packaging material (primary packaging material) affects stability of drug/formulation. Alkaline nature of glass may affect the drug pH stored in the container. The pharmaceutical preparations are pH sensitive agents that may lose their efficacy if any changes take place in their pH. Alkali metals may leach through the container and interfere with drug stability, efficacy and potency. So, it is necessary to determine whether the alkalinity of glass complies with limits prescribed in official monograph.

General test:

General test Take 5-10grams of glass pieces and ground them Pour the ground mass in a flask and add methyl red solution sufficient enough to dip the glass Reflux for 10-12minutes with reflux condenser Change of colour from red to yellow indicate alkalinity of the glass

Tests for alkalinity of the glass:

Tests for alkalinity of the glass

Apparatus and reagent:

Apparatus and reagent APPARATUS: Autoclave : with thermometer, pressure gauge, vent cock and rack for at least 12 containers Mortar and pestle Other equipment: Sieves of various mesh with pan & cover, conical flasks, hammer, magnet and volumetric apparatus REAGENTS: Highly pure water, Methyl red solution (indicator ), acid Note : Wear gloves, goggles and safety dress

1- Powdered glass test:

1- P owdered glass test

PowerPoint Presentation:

STEP 1: PREPARATION OF THE SAMPLE Rinse 6 or more containers with purified water and dry with stream of dry air. Crush them into tiny pieces (25mm in size) Make 3 portions (each portion weighing 100grams) A dd one portion of the glass pieces in the mortar and crush them with hammer, Pass them through the sieve no. 20 and repeat the procedure with the remaining portions Repeat the crushing and sieving and finally pass them through a nest of sieves shaken on a mechanical shaker for 5minutes. Transfer the portion retained on the sieve no. 50 which shall weigh in excess of 10grams in a closed container. Store in the desiccator until used.

PowerPoint Presentation:

STEP 2: REMOVAL OF IMPURITIES Spread the sample on a piece of glazed paper and pass magnet through it to remove metal/iron particles Transfer the sample to 250ml conical flask and wash with 6 30ml portions of acetone Dry at 140°C for 20minutes and use the sample within 48hours of drying

PowerPoint Presentation:

STEP 3: PROCEDURE (WATER TREATMENT) Take 10gram of prepared sample in 250ml conical flask (previously digested/aged with high purity water) Add 50ml high purity water to the flask and to the one that is prepared similarly to act as a blank Cap the flasks with previously treated borosilicate glass beakers, place in autoclave and heat vigorously for 10minutes Adjust the temperature so that it raises 1° per minute until it reaches 121°C taking 19-23minutes. Hold the temperature at 121°C ± 0.5°C for 30minutes Cool the flasks at once under running water Decant the water and wash the residue with 4 15ml portions of high purity water

PowerPoint Presentation:

STEP 4: TITRATION (ACID-BASE TITRATION) Add 5 drops of methyl red solution and titrate immediately with 0.02N sulphuric acid The volume of sulphuric acid used should not be exceeding the specified limit.

2- Water attack test:

2- Water attack test

PowerPoint Presentation:

Rinse thoroughly, 2 or more container, twice with high-purity water. PROCEDURE: 1- Fill each container 90% of its overflow capacity with high purity water. 2- Autoclave as mentioned in powdered glass test for 1hour. 3- Take 100ml of the content from one or more container in a 250ml conical flask of resistant glass. 4- Add 5 drops of methyl red solution and titrate with 0.02N H 2 SO 4 . 5- Complete the titration within 60minutes of opening of the autoclave. 6- The volume used must not be more than the specified limit.

PowerPoint Presentation:

SPECIFICATIONS TYPE GENERAL DESCRIPTION TYPE OF TEST LIMITS SIZE (ml) ml OF 0.02N SULPHURIC ACID I Highly resistant borosilicate glass Powdered glass test All 1.0 II Treated soda-lime glass Water attack test 100 or less Above 100 0.7 0.2 III Soda-lime glass Powdered glass test All 8.5 IV General purpose soda-lime glass Powdered glass test All 15.0

TOXICITY TEST:

TOXICITY TEST

Toxicity :

Toxicity The quality of being poisonous due to presence of a toxic substance is called toxicity. Toxoid A toxin treated by heat or chemical agent to destroy its deleterious properties without destroying its ability to stimulate antibody production

Toxicity tests:

Toxicity tests These tests are carried out to determine the presence of toxins in a preparation. Toxicity tests should be performed for all types biologicals, infusions, their containers and their stoppers.

Toxicity tests for vaccines:

Toxicity tests for vaccines

1- Test for Diphtheria toxoid:

1- Test for Diphtheria toxoid Inject subcutaneously the diphtheria toxoid to four healthy guinea pigs each weighing 300-400grams with a volume of at least 5times the intended human immunization dose; but less than 2ml. According to the requirements of this test, no local or general symptoms of diphtheria toxin poisoning shall appear within 30days.

2- Test for Tetanus toxoid:

2 - Test for Tetanus toxoid Inject subcutaneously, not less than 4 healthy guinea pigs each weighing 300-400gram with a volume of tetanus toxoid at least 5times the intended human immunization dose but not less than 2ml. No symptoms of tetanus toxin poisoning should appear within 21 days.

Toxicity tests for rubber closure (NF method):

Toxicity tests for rubber closure (NF method)

1- Acute systemic toxicity test:

1- Acute systemic toxicity test Take mice as a test model and inject the extract intra-peritonealy or intravenously. Observe the mortality or gross toxicity following the injection of the extract. 2- Intracutaneous reactivity test Take albino rabbits as a test model and inject the extract intra- cutaneously . Note the sign of toxicity at the site of injection e.g. edema, erythema, necrosis or redness

Abnormal toxicity testing (BP method):

Abnormal toxicity testing (BP method) Method A must be preferred unless otherwise stated

1- Method A:

1- Method A Take 5 mice and inject intravenously each of them with the injection limit of preparation as specified in monograph. Time of injection should normally be 15-30minutes unless otherwise stated in monograph. None of the mice should die within 24hours or within the time specified in the monograph. If one of the mice dies within time specified, repeat the test with same number of animals. None of the mice in the second test group should die within the time specified.

2- Method B:

2 - Method B Unless otherwise stated in monograph, inject 0.5ml of the extract intraperitoneally to each of 5 mice and 5ml of the extract intraperitoneally to each of 2 guinea pigs. None of the animal should die or show any symptoms of illness within 7 days. If one of the animal dies or shows illness within 7 days, repeat the test None of the animal in the second group should die within 7 days.

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