A more refined method for determining residual solvents and volatile impurities is based on head space analysis.
The simplest method of sampling is to put the sample into a sealed vial and heat it as shown in Figure 11.23. The sample, either in solution or slurried with a relatively involatile solvent with little potential for interference, e.g. water, is put into a sealed vial fitted with a rubber septum and heated and agitated until equilibrium is achieved. Then a fixed volume of head space, e.g. 1 ml is withdrawn. The sample is then injected into a GC in the usual way. If capillary column GC is used a split injection has to be used to facilitate sample injection; a flow of 10:1 out of the split vent would ensure that a 1 ml sample could be injected in about 5 s with the flow through the column being 1 ml/min. Several points are important to note:
(i) Partition equilibrium must be established by heating for an appropriate length of time and at an appropriate temperature
(ii) A clean room is required away from all other sources of volatiles such as laboratory solvents
(iii) Potential interference from rubber septa must be checked
(iv) Reactive contaminants may react with the sample matrix at high temperatures
(v) If the sample is ground and mixed in preparation for the head space analysis care has to be taken to ensure that no volatiles are lost.
For best reproducibility the process should be automated and for quantitative accuracy it would be best to use the method of standard additions (Ch. 6 p. 123). Suitable columns include packed columns containing Porapak Q or long thick film (3-5 ¿urn) capillary columns, which for best selectivity should be coated with a phase which is moderately polar to polar.
Figure 11.24 shows a chromatographic trace for residual solvents in a sample of cephalosporin obtained by automatic sampling of the head space in a sealed vial.8 The cephalosporin sample (300 mg) was suspended in diethylene glycol (DEG) (the low vapour pressure of this material meant that it was not present in large amounts in the head space).
Methanol Ethanol y
Ethyl DEG Diethylether acetate
Solvent impurities in cephalosporin analysed by sampling of the head space above a heated DEG solution of the drug. Separation was carried out on column (10 feet x 1/8 in i.d.) packed with Porapak Q. Reproduced with permission from J. Chromatology (see Reference 8).
Which of the following capillary columns would be most suitable for use in the determination of residual solvents by head space analysis (consult Table 11.1):
(ii) OV-17 column 15 m x 0.33 mm i.d. x 0.5 fjm film
(iii) OV-225 column 30 m x 0.5 mm i.d. x 3 /jm film
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