Pharmaceutical Chemistry PDF : IMPURITIES IN PHARMACEUTICALS
1.1 Introduction
This course is designed to provide basic knowledge on the chemical structure storage conditions and medicinal uses of organic and inorganic chemical substance used as drug and pharmaceuticals. Also, this course discusses the impurities, quality control aspects of chemical substances used in pharmaceuticals.
1.1.1 Course Objectives
This course will discuss the following aspects of the chemicaltoSubstances used as drugs and pharmaceuticals for various disease conditions –
- Chemical classification, chemical name, chemical structure
- Pharmacological uses, doses, stability and storage
- Different types of formulations / dosage form available and their brand names
- Impurity testing and basic quality control tests
1.1.2 Scope
The development and formulation of drugs for treating patients with diseases and researching how different chemicals affect various biological systems are the various fields in which the pharmaceutical chemistry can be applied. The drug applications from pharmaceutical companies are reviewed by the chemists at the US Food & Drug Administration or the FDA. Additionally, synthetic pharmaceuticals and analytical pharmaceuticals are the two distinct fields of Pharmaceutical Chemistry.
New drugs and products are created by synthetic pharmaceutical chemistry in the most cost-effective way that generates the least amount of negative side effects. The design is given and the methods are applied by the analytical pharmaceutical Chemistry to a product to ensure that the drug is refined.
1.2 Error
Error is the difference between measured value and true value. Though the measurements are made by different methods of quality control, systematically and carefully but there is some degree of error.
1.2.1A Sources of Error
- Instrumental error happens when the instruments being used are inaccurate, such as a balance that does not work. A pH meter that reads 0.5 off or a calculator that rounds incorrectly would be sources of instrument error.
- Environmental error happens when some factor in the environment, such as an uncommon event, leads to error. For example, if you are trying to measure the mass of an apple on a scale, and your classroom is windy, the wind may cause the scale to read incorrectly.
- Procedural error occurs when different procedures are used to answer the same question and provide slightly different answers. If two people are rounding, and one rounds down and the other rounds up, this is procedural error.
- Human error is due to carelessness or to the limitations of human ability. Two types of human error are transcriptional error and estimation error.
- Transcriptional error occurs when data is recorded or written down incorrectly. Examples of this are when a phone number is copied incorrectly or when a number is skipped when typing data into a computer program from a data sheet.
- Estimation error can occur when reading measurements on some instruments. For example, when reading a ruler you may read the length of a pencil as being 11.4 centimeters (cm), while your friend may read it as 11.3 cm.
1.2.1B Classification of error
- Determinate errors/systematic errors: These types of errors aredeterminable and can be either avoided or corrected –
- Instrumental error: It is caused by use of faulty equipment.
- Personal error: It is the error made by person doing analysis.
- Chemical error: This error is due to impurities in chemicals.
- Methodological error: It arises due to faulty method used for analysis,
g. Incomplete reaction, incomplete heating. - Indeterminate errors/random errors: These errors are also called accidental errors. These errors are fluctuating and do not have a definite value and are difficult to locate. They arise due to unknown or uncertain measurement or may be due to difference in judgment and skill of analyst.Hence,elimination of these errors is impossible to the analyst.
1.2.2 Accuracy
Nearest or accurate value which are matches to the true value of any experiments is defined the term accuracy.
Accuracy is also described as degree of agreement between a measured value and the accepted true value. In scientific experiments, since no measurement is completely accurate, the true value is not known within certain limits. It is the simple taken as a value that has been accepted and is generally a mean calculated from the results of several determinants from many laboratories using different techniques.
The comparison is normally done with regard to the error and the accuracy is inversely proportional to the error
1.2.3 Precisions
Precisions are defined as the agreement amongst a cluster of experimental results; however, it does not imply anything with respect to their relation to the ‘true value’ precisions designates ‘reproducibility’ of a measurement, where accuracy, but ironically a high degree of precision may not necessarily suggest accuracy.
Precision define the ranging nearest value of any experiment to the initial value.
Example—Analyst perform the experiment on milk with respect to water and conclude that—88.3, 85.4, 86.8, 88.5, 87.9.
Actual water percentage in milk is 87,Thenprecision range is—85.4 to 88.5.
1.2.4 Significant figures
In the analysis, significant figures play a very important role in accuracy and precision. The number of significant figures can be defined as, “the number of digits necessary to express the result of a measurement consistent with the measured precision”.
Significants | Non – Significants |
All non-zeros are significant Eg. 1,2,3,4,5,6,7,8,9 | All starting zeros are non-significant E.g. 0.0123, 0.00001 |
Trapped zeros/zeros appearing in between non-zero digit are significant E.g101, 2003, 0.01004, 90.001 | All ending zeros without decimal points are non-significants Eg. 100, 55600, 50100 |
Ending zero with a decimal point are significant E.g. 6.300, 50.000, 56.60 |
How to minimizing the errors–
- Calibration of Instruments, apparatus.
- Personal care (skilled) required.
- Choosing the suitable and usable materials.
- Exhausted the impurities contamination.
- Study chemical evaluation and analysis.
- Proper methodology.
1.3 IMPURITIES
Impurity is the undesirable foreign material which may be toxic or may not be toxic, present in the pharmaceutical substances.
Chemical purity implies the freedom from impurities but it is rather difficult to obtain an almost 100% pure substances.
1.3.1 | SOURCES OF IMPURITIES |
The type and amount of impurity present in pharmaceutical substances depend upon several factors:
- Raw material used in the manufacture
- Process used in the manufacture
- Material of the plant
- Inadequate storage
- Manufacturing hazards
- Deliberate adulteration
a) Raw material used in the manufacture: The raw materials used for the manufacturingof pharmaceutical products, often contain impurities. These impurities may come in the final product
Example:
i) Metallic zinc may be present as impurity in Zinc oxide sample.
ii) Sodium chloride prepared from rock salt will almost contain traces of calcium and magnesium compounds.
B) Process used in the manufacture:Impurity comes during manufacturing process. For example;
i) Tap water is frequently used in various manufacturing process. This tap water contains chloride, calcium and magnesium which may come as impurities in the final product.
ii) During manufacturing process, because of wide use of strong acids (HCl, H2SO4). Chloride and Sulphate ions are very commonly occurring impurities.
C) Material of the plant: The manufacturing equipment (or) utensils are made up of metals like copper,aluminium, iron or stainless steel. Due to solvent action on the equipment, the traces of metals are introduced as impurities.
D) Inadequate storage: Stored products may be contaminated with dust, insects and even animal and insect excreta. Due to careless storage some chemical substances undergo chemical changes and decompose. Ex: Ferrous sulphate is slowly converted into insoluble ferric oxide by air and moisture.
E) Manufacturing hazards: Include Particulate contamination, process errors, cross contamination, microbial contamination, packing errors etc.
E) Deliberate adulteration: Mostly drug are mixed with cheaper drug. Ex: KBr is used as sedative is often mixed with NaBr
1.4 | LIMIT TEST |
Limit test are quantitative or semi-quantitative tests designed to identify and control small amount of impurities, which are likely to be present in the substance. They involve simple comparisons of opalescence, turbidity or color produced in the test with that of fixed standards. Some of the limit tests are performed in a special apparatus known as Nessler cylinder.
1.4.1 | LIMIT TEST FOR CHLORIDE |
Principle: Limit test for chloride is based upon the simple reaction between silver nitrate and soluble chlorides (if present in the sample) to give insoluble silver chloride in the presence of dilute nitric acid.
The insoluble silver chloride makes the solution opalescent and the extent of opalescence is compared with a standard opalescence produced in a standard solution having a known amount of chloride.
If the opalescence produced in the test is less intense than that of standard opalescence, the sample passes the limit test for chloride and vice versa.
Chemical reaction:
Cl– + AgNO3Dil.HNO3AgCl + NO3–
silver nitrate Dilute Nitric acid silver chloride
Role of reagent:
Dilute nitric acid is used to prevent the opalescence of other acid radicals with silver nitrate solution.
Procedure:
SAMPLE SOLUTION | STANDARD SOLUTION | ||
1 | 1ml of sample is dissolved in water and transfer to a Nessler cylinder | 1 | Pipette out 1ml of standard NaCl solution and transfer into Nessler cylinder. |
2 | Add 10ml of dilute HNO3 | 2 | Add 10ml of dilute HNO3 |
3 | Add 1ml of AgNO3 solution stir immediately with a glass rod | 3 | Add 1ml of AgNO3 solution stir immediately with a glass rod |
4 | Dilute upto 50ml with water and kept aside for 5 minutes. | 4 | Dilute upto 50ml with water and kept aside for 5 minutes. |
Result
The opalescence produced by a given amount of the substance is compared with the standard opalescence.If the opalescence produced in the sample is less than the standard opalescence, the sample passes the limit test and vice versa.
1.4.2 | LIMIT TEST FOR SULPHATE |
Principle:Limit test for sulphate depends upon the interaction of soluble sulphates (if present in the sample) with barium chloride in the presence of dilute hydrochloric acid to produce turbidity due to formation of insoluble barium sulphate (BaSO4) precipitate.
Role of Reagent:
Barium Sulphate reagent (It consists of barium chloride( ), alcohol and a very small amount of Potassium Sulphate, KI)
- a) Barium Chloride: To produce turbidity
- b) Alcohol: Prevents supersaturation and thereby produce uniform turbidity.
- c) Potassium Sulphate( : Increase the sensitivity of the test by giving ionic concentration in the reagent.
Procedure:
SAMPLE SOLUTION | STANDARD SOLUTION | ||
1 | Dissolve the specified quantity of a substance in water and transfer to a Nessler cylinder | 1 | Pipette out 1ml of 0.1089%w/v solution of Pot. Sulphate (standard solution) in Nessler cylinder |
2 | Add 2ml of dil. HCl | 2 | Add 2ml of dil. HCl |
3 | Add 5ml of Barium sulphate reagent stir immediately | 3 | Add 5ml of Barium sulphate reagent stir immediately |
4 | Diluteupto 45ml with water and kept aside for 5 minutes | 4 | Dilute upto 45ml with water and kept aside for 5 minutes |
Note: dil. HCl is added, except where HCl is used in the preparation of standard solution (or) test sample solution. Dil.HCl is added to dissolve other impurities like carbonates & phosphates are also present in the sample.
Result
The turbidity/precipitate produced by a given amount of the substances is compared with the standard turbidity.
If the turbidity produced in the sample is less than the standard turbidity, the sample passes the limit test and vice versa.
1.4.3 | LIMIT TEST FOR IRON |
Principle:-The limit test for iron is based on the reaction between iron and thioglycolic acid in the presence of strong ammonia solution and citric acidwhich gives pale pink to deep reddish purple colour due to the formation of ferrous thioglycolate complex.
Role of Reagent:
- a) Thioglycolic acid- Strong reducing agent which reduces ferric to ferrous ion and form ferrous thioglycolate complex.
b)Citric acid- Prevent precipitation of iron with ammonia by forming its own complex with ammonia.
- c) Ammonia-Formation of ferrous thioglycolate takes place only in the presence of strong alkali or certain oxidizing agents; therefore, strong ammonia solution is used to provide an alkaline medium.
Procedure:
SAMPLE SOLUTION | STANDARD SOLUTION | ||
1 | The specified quantity of sample is dissolved in water and transferred to a Nessler cylinder | 1 | Pipette out 2ml standard ferric ammonium sulphate solution into a Nessler cylinder |
2 | Add 2ml of 20%citric acid | 2 | Add 2ml of 20%citric acid |
3 | Add 0.1ml of thioglycolic acid | 3 | Add 0.1ml of thioglycolic acid |
4 | Make up the solution alkaline by adding the ammonia. | 4 | Make up the solution alkaline by adding the ammonia. |
5 | Make up the volume up to50ml by adding water. | 5 | Make up the volume up to50ml by adding water. |
6 | Allow to stand for 5 minutes | 6 | Allow to stand for 5 minutes |
Result
The colour produced by a given amount of the substance is compared with the standardcolour.If the intensity of color produced by the sample is lesser than the standard color, the sample passes the limit test and vice versa.
1.4.4 | LIMIT TEST FOR HEAVY METALS IP |
Principle: Limit test for heavy metals is based on the reaction of metallic impurities with hydrogen sulfide in the presence acidic medium to form brownish colour solution
Procedure
SAMPLE SOLUTION | STANDARD SOLUTION | ||
1 | The specified quantity of sample 25ml is transferred to a Nessler cylinder | 1 | Pipette out 2ml standard lead solution and dilute with 25ml of water |
2 | Add dilute acetic acid/ammonia to adjust the pH between 3 and 4 | 2 | Add dilute acetic acid/ammonia to adjust the pH between 3 and 4 |
3 | Add water upto 35 ml | 3 | Add water upto 35 ml |
4 | Add 10ml of H2S solution | 4 | Add 10ml of H2S solution. |
5 | Dilute it upto 50 ml of water . | 5 | Dilute it upto 50 ml of water. |
6 | Allow to stand for 5 minutes& observe the turbidity | 6 | Allow to stand for 5 minutes& observe the turbidity |
Result:
The colour produce in sample solution should not be greater than standard solution. If colour produces in sample solution is less than the standard solution, the sample will pass the limit test of heavy metals and vice versa.
1.4.5 | LIMIT TEST FOR ARSENIC |
Principle:
The limit test for arsenic is based on the reaction of the arsenic in the arsenious state to the arsine gas ( ) with zinc(Zn) and hydrochloric acid (HCl) in the presence of Potassium iodide(KI).The arsine gas stains the mercuric chloride (Hg paper to yellowish brown stain which is compared with standard stain.
Note: The arsenic acid is reduced to arsenious acid by reducing agents like Potassium iodide(KI), stannous acidSn .
Chemical Reaction:
- Role of Reagents
- i) GranulatedZinc and HCl– Gives nascent hydrogen
- ii) Stannous Chloride (SnCl2) – essential for complete evolution of arsine gas.
iii) Potassium iodide – Reducing agent (helps in reducing tetravalent Arsenic acid to trivalent Arsenic acid)
- iv) Lead-Acetate Cotton Plug [Pb(CH3O2)2 – It is used to trap any hydrogen sulphide H2S (which react with mercuric chloride (HgCl2) paper producing a dark stain) which may be evolved along with arsine gas.
Apparatus (Gutzeit Apparatus)
It consists of a widemouthed bottle of 120ml capacity fitted with a rubber bung through which insert a glass tube of length 200.0mm and internal diameter of 6.5mm and external diameter of 8.0mm. The lower part of the tube is constricted to an internal diameter of 1.0mm and 15.0mm from its tip. It hasa lateral orifice of 2.0mm in diameter. The upper end of the tube is closed with rubber bung. The mercuric chloride paper is placed between the bungs and clapped together with a clip.
Procedure:
- The glass is packed with lead acetate cotton.
- The solution of the sample is placed in the wide mouthed bottle
- To this add 1.0 g of Potassium iodide, 5ml of stannous chloride acid (SnCl2 solution and 10.0 g of zinc.
- Immediately place the glass tube in position and keep it on a water-bath for 40 minutes and maintain a temperature of 40o
- After 40 minutes, the yellow stain produced on the HgCl2 paper is compared with the standard stain produced by treating 1.0ml of the arsenic standard solution diluted to 50ml with water in the same manner.
- If the intensity of the yellow stain produced by the test solution is less than that of standard stain, the sample passes the limit test for arsenic & vice–versa
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1.4.6 |
LIMIT TEST FOR LEAD |
Principle: It is based on the violet color produced in chloroform due to the reaction between lead impurity and dithizone which result in the formation of lead dithionate. The intensity of final violet color produced in the chloroform medium is compared with standard.
Chemical reaction
Procedure:-
|
STANDARD SOLUTION |
SAMPLE SOLUTION |
||
|
1 |
Take specified volume of standard lead solution in a separating funnel as prescribed in the pharmacopoeia. |
1 |
Take the specified volume of a sample solution in a separating funnel. |
|
2 |
Add 6ml of ammonium citrate solution. |
2 |
Add 6ml of ammonium citrate solution. |
|
3 |
Add 2 ml of potassium cyanide and 2 ml of hydroxylamine hydrochloride solution. |
3 |
Add 2 ml of potassium cyanide and 2 ml of hydroxylamine hydrochloride solution. |
|
4 |
Add 2 drops of phenol red indicator. |
4 |
Add 2 drops of phenol red indicator. |
|
5 |
Make the solution alkaline by adding ammonia solution. |
5 |
Make the solution alkaline by adding ammonia solution. |
|
6 |
Extract with 5 ml of dithizone until it becomes green. |
6 |
Extract with 5 ml of dithizone until it becomes green. |
|
7 |
Combine dithizone extracts are shaken for 30 seconds with 30 ml of nitric acid and the chloroform layer is discarded. |
7 |
Combine dithizone extracts are shaken for 30 seconds with 30 ml of nitric acid and the chloroform layer is discarded. |
|
8 |
To the acid solution add 5 ml of standard dithizone solution. |
8 |
To the acid solution add 5 ml of standard dithizone solution. |
|
9 |
Add 4 ml of ammonium cyanide. |
9 |
Add 4 ml of ammonium cyanide. |
|
10 |
Shake for 30 seconds. |
10 |
Shake for 30 seconds. |
|
11 |
Compare the color (violet) developed. |
11 |
Compare the color (violet) developed. |
Result: The intensity of final violet color produced in the chloroform medium is compared with standard solution. If the sample solution produces less color than standard solution the test is passes for lead.
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1.4.6 |
Short Notes |
