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Salbutamol is a short acting ß2 adrenergic receptor agonist. It is a bronchodilator medicine used in conditions such as asthma, chronic obstructive pulmonary disease, emphysema, bronchitis and other lung related problems. Salbutamol acts by stimulating ß2 receptors in the airway and lungs. This stimulation results in the activation of adenylate cyclase and the subsequent increase in cAMP. These changes allow bronchial smooth muscle relaxation giving the patient help in breathing.
Chemical structure of Salbutamol 
Salbutamol Sulphate comes in many preparations including injections, dry powders for inhalation, tablets, and prolonged release tablets and capsules, aswell as the inhalation aerosol form and the oral solution.
In the UK, Ventolin® is probably the most familiar brand of Salbutamol Sulphate among patients. A syrup by this name is available and has a strength of 2mg/5ml Salbutamol Sulphate. An aerosol inhalation device is also marketed under this name and is 100mcg/metered inhalation of Salbutamol Sulphate.
Salbutamol Sulphate is a ‘white or almost white crystalline powder. It is sparingly soluble in water, but 96% soluble in ethanol. It has a melting point of about 155°C .’
Quality assurance, with reference to products can be explained as being; a system formed and put in place to guarantee a certain level of quality which is expected throughout product life. It is a system used many manufacturing industries in particular, as well as others too. It has been described as ‘a wide ranging concept covering all matters that individually or collectively influence the quality of a product.'
‘In the light of growing cross border health issues and the international dimensions of trade, quality assurance of pharmaceuticals is a major public health challenge .’
The World Health Organisation is taking a leading role in ensuring high levels of quality assurance in the pharmaceutical industry, and has divided quality assurance into four major areas; quality control, production, distribution and inspection.
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With reference to Salbutamol syrup and aerosol, and any other pharmaceutical product, quality assurance is essential for that product to be considered safe and acceptable for use by the general public. It is a key part of the process of manufacturing pharmaceuticals. In the case of Salbutamol, there are many tests required to be fulfilled at each stage of the products life. Syrups would have to go through strenuous testing, namely setting times, particle size, rheology, degree of flocculation, and pyrogen testing. Along with many more tests for quality at the time of manufacture, the syrup would then go through various packaging tests, distribution tests and then general inspections.
Some of the tests include batch testing, stress testing, photo-stability, light, glass checks moisture and climatic zone checks, as well as storage testing . The aerosol too would be under the same degree of testing throughout its life, with some different criteria to meet with respect to the formulation including particle size, simulation testing, and device mechanics.
In products such as syrups and aerosols, different excipients are used in the formulation. In syrups, excipients such as buffers, colourants, flavouring agents, sweeteners, thickeners and preservatives are all used. In aerosols hydrocarbons, carrier particles and solvents are common.
Evaluation of Techniques
After an overview of the techniques covered in the module, it was clearly evident that they all had their places in the determination of pharmaceutical agents. With respect to the question in hand and reference from the literature, I have come to the conclusion that the best methods of analysis for Salbutamol Sulphate are Flow Injection Analysis and Derivative Spectroscopy (including UV/Visible Spectroscopy).
Derivative spectroscopy ‘involves the transformation of absorption spectra into first-, second-, or higher order derivative spectra .’ This technique has been used more than once in the analysis of Salbutamol. The rate of change of absorbance with the respect to wavelength is the first order derivative. A first order derivative is also known as ‘zero order’ as it starts and finishes at zero. The difference between a first order and second order derivative is that the second order derivative has a negative trough at the same wavelength as the zero order maximum wavelength.
It is assumed Beer’s Law is applied to the zero order spectrum, so it can be said that the peak heights or peak to trough distances on derivative spectra are proportional to concentration .
Mathematical, Optical or Electronic methods are used to obtain derivative spectra. Optical derivitisation using rapidly modulated wavelengths of incident light are only used to get upto the second derivative. Electronic techniques using resistance capacitance devices help to attain higher order derivatives. Using mathematical techniques, the first derivative can be calculated by establishing the difference in absorbance between two neighbouring wavelengths. Using the principle that dA/dÎ» is the first derivative and that d2A/dÎ»2 is the second derivative, higher order derivatives can be established by linear interpolation between wavelengths.
More commonly a method by Savitzky and Golay using the least squares method is used . As higher derivatives are calculated spectra can become complicated however the advantage here is that identification and analysis is easier. At what may seem a single peak on an absorbance spectrum may give several peaks once derivatised.
Mukherji & Aggarwal printed their work in 1991 regarding the Determination of Salbutamol in the presence of Gelatine using Derivative Spectroscopy. Using derivative spectroscopy they were able to go upto the fourth derivative, and tested fixed concentrations of salbutamol in the presence of varying gelatine concentrations. They used the first, second and fourth derivative and spectra showed clear overlap between bands of different gelatine solutions. They concluded their study by establishing the different concentrations the drug can be analysed at, at each different derivative .
Mukherji & Aggarwal continued this work, and devised a method to estimate salbutamol in the presence of albumin by derivative UV spectroscopy. Using there experience in the field from previous work, the second and fourth derivative was again obtained and analysed. They analysed solutions of different concentrations of both salbutamol and albumin. Again, the conclusions drawn were interesting, establishing that the zero order system gave much interference. Also noted was that the second order system showed much improvement and the fourth derivative showed that this method can’t be used for salbutamol under concentrations of 8Î¼g/ml. Some higher derivatives taken showed similar findings to the second derivative results .
A disadvantage of using derivative spectra is that small wavelength errors can result in larger signal errors when derivatizing in comparison to a normal absorption spectrum. Also when not using the Savitzky & Golay method the data cannot be smoothed, this helps in approximating data points.
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When using higher order derivatives the signal to noise ratio decreases. This is important as ‘noise contains the sharpest features in the spectrum’ . Some methods have been used to reduce the loss of the signal to noise ratio and include the use of ‘a reference wavelength or a full spectrum multicomponent analysis with a scattering spectrum as a standard .’
An advantage is the ability to ‘discriminate.’ This is a discrimination of broad bands. This helps when analysing two bands with similar bandwidth. When derivatizing the bands the true make-up of the band is seen. The main advantage though is the ability to be able to produce derivatives of spectra and unmask the analyte of interest. Surviving background effects are eliminated using higher derivatives.
Due to recent developments in derivative ultraviolet/visible absorption spectroscopy, much work has been done using this technique when analysing pharmaceutical agents. It has been a popular choice mainly due to its ability to permit discrimination against broadband interferences, and its ability to be combined with another technique .
Other work has been done using direct UV analysis and has produced posotive results in the fact that salbutamol can be analysed alone, eliminating effects from excipients, by using anion exchange chromatography prior to analysis. In 1995 Sadler & Jacobs investigated the use of the Folin-Ciocalteau reagent to determine salbutamol in pharmaceutical preparations. Salbutamol’s chemical structure has a phenol group which has the potential to be reduced. The Folin-Ciocalteau reagent acts as a chromogenic reagent enabling the sample to form various unstable derivatives, monitoring their absorbance at a fixed wavelength . Here the effect of the excipients will have an effect on the spectra. Excipients can cause broad featureless absorption. This absorbance measured of the excipient affects the absorbance result of the sample of interest. The absorbance is not that intense and isn’t a problem when the drug is present in high concentrations. Background absorbance can be reduced by diluting the sample, still giving good spectra for the analyte. When the drug in the sample has low absorptivity, or is in very small concentrations in comparison with the excipients, background absorbance is still a problem . ‘Deuterium or Hydrogen lamps are commonly radiation sources. Cuvettes are generally made from quartz or fused silica .’
UV-VIS absorption equipment used in research is either of the scanning spectrophotometric type or the dual beam type. The dual beam method is quicker and has an added advantage of being able to take into account any fluctuations when calculating data ratios. The use of photomultiplier tube detectors enable the instrument to have a high resolving power, however it is slower than the dual beam method .
FIA is a technique that is ‘based on the injection of the liquid sample into a moving, nonsegmented continuous carrier stream of a suitable liquid.’ The sample is transported to a detector recording the absorbance .’ Typical instrumentation includes ‘a peristaltic pump, an injection valve, a coiled reactor, a detector and an autosampler .’
In 2004 work was presented by Dol & Knochen, in which they proposed a flow injection method for the determination of salbutamol. After evaluation of the use of UV Sectrophotometry it was concluded that this method will not be used mainly due to the presence of unwanted background reading from excipients.
Generally excipients in syrups like those mentioned above are notorious for causing many problems in analysing a drug within its formulation. The results for the drug may be masked within the results obtained from the excipients. Due to the ‘analyte being influenced by additive interference causing spectral overlap, the UV method does not apply to oral solutions where the combined spectra of sweeteners, flavours and colourants produce a considerable additive interference .’ However UV spectrophotometers are commonly linked to FIA equipment. Again, due to salbutamol being a phenol, the ability to produce a chromophore for analysis may increase selectivity. Dol & Knochen used a well known reaction to determine the phenol involving 4-aminoantipyrine in the presence of an oxidant like hexacyanoferrate (III). This reaction produces a coloured quinoneimide which is detected by a UV spectrophotometer.
Flow injection analysis has been used successfully in the determination of salbutamol and produced good results. It is a technique developed in 1970’s and is being used more and more by chemists worldwide. It provides advantages of being simple to use and relatively low cost of instrumentation. FIA also produce a high sample rate and is cost effective to use. Advantages include automated sample preparation which improves precision, and high quality detection. Common detectors are fluorimeters and colorimeters; however the equipment is capable of being linked to many various detector systems, giving another potential plus point of using the technique. The peristaltic pump must be checked, and the tubing must be routinely replaced. Sample sizes can range from 5-200µL, but are more likely to be 10-30µL in reality. The sample must be injected rapidly, but not so it disturbs the flow of the carrier stream. Detection can be carried out in many different forms including electrochemical systems and refractometers. Temperature and flow rate must be monitored also .
‘FIA is capable of precision better than 1%. This is a as a result of extremely controlled sample dispersion in a continuous flowing stream .’
Further advantages are the possibility to make additions to the equipment. For example, ‘the speed of chemical reactions can be increased with the addition of a flow through heater, the addition of columns for sample reduction, the use of debubblers, and filters for particulate removal .’
The aerosol releases 100mcg per dose. This is a very small amount of drug in physical terms and the presence of excipients can cause further problems when analysing the active agent. It is known that particles size must be less than 10Î¼m for a particle to be successfully placed in the lungs. Particle size tests are important for formulations in inhalation, as too is microbe testing, device testing and aerosol time of flight mass spectrometry. This testing ensures the device is releasing the required dose and is easy to use, and that the drug in the formulation is not damaged and meets all stability criteria set on production, and so is pharmacologically active or is ready to be activated upon taking.
‘The most recent official BP and USP assays for salbutamol aerosol are based on HPLC and non-aqueous titration .’ In terms of sample preparation the BP’s method is most favourable. The aerosol is cleaned to remove all solvents and placed in a stainless steel base plate with a 1.5mm indentation. The inhaler is discharged 10 times into an appropriate solvent to collect the drug. The solution is mixed with a mixture of methanol and water and then ammonium acetate, and made to 100ml. HPLC is then used to calculate the amount of drug in 10 actuations . This solution can now be diluted or altered to be used in other techniques.
Another method from the literature is for dry powder inhalers. Here the inhalers were placed in fume cupboards to evaporate the propellants and leave the drug powder for analysis .
For syrups, sample preparation is simpler. The BP advises liquid chromatography as its preferred analysis technique, and advises to use 5mg of salbutamol to produce a 50ml mobile phase to be passed through a filter to produce a filtrate. The filtrate is then used for chromatography using silica gel. When determining salbutamol in pharmaceutical preparations, Sadler and Jacobs, simply measured a volume of syrup equivalent to 5mg salbutamol with an equal volume of water, passed the solution through a chloride resin and collected 100ml of eluant. Further to this specific aliquots were prepared for analysis .
In summary, the techniques described above are a great tool to analytical chemists who need to determine the presence of different pharmaceutical agents in different solutions or formulations. They all have their own benefits and drawbacks. The use of derivative spectroscopy has enabled us to remove levels of background reading and analyse individual peaks on spectra. UV spectroscopy also has been shown to be a useful tool in analysis. With particular sample preparation, background readings can be reduced but is still a major cause of inaccuracy in some analysis. FIA is being used more and more in the environmental and agricultural industries with success, aswell as in E.coli monitoring, Solid Phase Extraction and Oceanographic research.
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