Physical Constants - Pharmaceutical Chemicals: Management

PHYSICAL CONSTANTS

A wide range of physical constants, for instance : melting point, boiling point, specific gravity, viscosity, refractive index, solubility, polymorphic forms vis-a-vis particle size, in addition to characteristic absorption features and optical rotation play a vital role in characterization of pharmaceutical chemicals and drug substances. These physical constants will be discussed briefly with typical examples as under :

1. Melting Point

It is an important criterion to know the purity of a substance ; however, it has a few limitations. The accuracy and precision of melting point is dependent on a number of factors such as—capillary size, sample size, initial temperature of heating-block and the rate of rise of temperature per unit time (minutes). Keeping in view the different manufacturing processes available for a particular drug the melting point has a definite range usually known as the melting range.

Thus the melting range takes care of the variance in manufacture together with the storage variance over a stipulated period of time.

2. Boiling Point

It is also an important parameter that establishes the purity of a substance. Depending on the various routes of synthesis available for a substance a boiling point range is usually given in different official compendia.

3. Refractive Index

It is invariably used as a standard for liquids belonging to the category of fixed oils and synthetic chemicals.

4. Weight Per Millilitre

Weight per millilitre is prevalent in the Pharmacopoeia of India for the control of liquid substances, whereas Relative Density (20°/20°) or Specific Gravity is mostly employed in the European Pharmacopoeia.

5. Specific Optical Rotation

As pharmacological activity is intimately related to molecular configuration, hence determination of specific rotation of pharmaceutical substances offer a vital means of ensuring their optical purity.

6. Light Absorption

The measurement of light absorption both in the visible and ultraviolet range is employed as an authentic means of identification of offcial pharmaceutical substances.

7. Viscosity

Viscosity measurements are employed as a method of identifing different grades of liquids.

8. Specific Surface Area

The surface area of powders is determined by subsieve-sizer which is designed for measurement of average particle sizes in the range of 0.2 to 50 microns. The relationship between average particle diameter and specific surface area (SSA) is given by the following expression :

where, SSA = Specific surface area in cm² per g of material

d = Average diameter in microns

p = True density of material from which the powder was made in g per cm³

9. Swelling Power

The swelling power of some pharmaceutical products are well defined.

Examples :

(i) Isphagula Husk : When 1 g, agitated gently and occasionally for four hours in a 25 ml stoppered measuring cylinder filled upto the 20 ml mark with water and allowed to stand for 1 hour, it occupies a volume of not less than 20 ml and sets to a jelly.

(ii) Heavy Kaolin : When 2 g is titurated with 2 ml of water the mixture does not flow.

10. Infrared Absorption

Measurement and subsequent comparison of the infrared spectrum (between 4000-667 cm^–1) of compounds with that of an authentic sample has recently become a versatile method for the identification of drugs having widely varying characteristics.

Examples : Infrared spectroscopy is employed to compare samples of chloramphenicol palmitate (biologically active form) recovered from chloramphenicol palmitate mixture vis-a-vis an artificially prepared mixture of authentic sample consisting 10 per cent of the ‘inactive polymorph’.

Infrared spectra of known and newly reported compounds are provided in the British Pharmacopoeia (1998) and also in ‘Sadtler Standard Spectra’ published by Sadtler Research Laboratories, Philadelphia

(USA) is available to check the authenticity of pure drug samples.

11. Miscellaneous Characteristics

A large number of miscellaneous characteristics are usually included in many official compendia to ascertain the purity, authenticity and identification of drugs—including : sulphated ash, loss on drying, clarity and colour of solution, presence of heavy metals and specific tests.

11.1. Sulphated Ash

Specifically for the synthetic organic compounds, the Pharmacopoeia prescribes values for sulphated ash. The sulphated ash is determined by a double ignition with concentrated sulphuric acid. Metals thus remain as sulphides that are usually stable to heat. The method is one of some precision, and provides results which are rather more reproducible than those obtained by simple ignition.

11.2. Loss on Drying

Loss on drying reflects the net weight of a pharmaceutical substance being dried at a specified tempera-ture either at an atmospheric or under reduced pressure for a stipulated duration with a specific quantity of the substance.

11.3. Clarity and Colour of Solution

When a pharmaceutical substance is made to dissolve at a known concentration in a specified solvent it gives rise to a clear solution that may be either clear or possess a definite colouration.

11.4. Heavy Metals

Various tests are prescribed in the offcial compendia to control heavy metal e.g., Ag⁺, Hg²⁺, Pb²⁺, Bi²⁺, Cu²⁺, As³⁺, , Sb³⁺ and Sn⁴⁺ contamination in organic pharmaceutical substances. Hence, a stringent limit is recommended for the presence of heavy metals in medicinal compounds.

11.5. Specific Tests

In fact, certain known impurities are present in a number of pharmaceutical substances. The presence of such impurities may be carried out by performing prescribed specific tests in various official compendia in order to ascertain their presence within the stipulated limits.

Reagents :

·              Dilute 1 ml N. HCl and 2.0 ml ferric ammonium sulphate soln. (10% w/v in H₂O) with suffcient water to produce 100 ml.

·              Dissolve 50 mg cadmium acetate in a mixture of 5 ml DW and 1 ml glacial acetic acid and dilute with ethyl methyl ketone to 50 ml. Immediately before use add and dissolve suffcient Ninhydrin to produce a soln. containing 0.2% w/v.

·              Dissolve 10.0 g sodium tungstate and 2.5 g sodium molybdate in 80.0 ml DW in a 250 ml flask; add 5.0 ml phosphoric acid (85-90% w/w) and 10.0 ml HCl (= 11.5 N), connect to a reflux condenser and heat for 10 Hrs. Cool, add 15.0 g lithium sulphate, 5.0 ml DW and 1 drop of bromine and allow to stand for 2 Hrs. Remove the excess bromine by boiling the mixture for 15 mts. without the condenser. Cool, filter and dilute with DW to produce 100 ml.

Caution :

(i) The prepared soln. should be stored below 4°C, and

(ii) The soln. should be used within 4 months after preparation till it retains its original golden yellow colour. It must be rejected if it has a trace of green colour.