Pharmaceutical Aerosols: Types, Features, Quality Controls, and Uses

Abstract

Pharmaceutical aerosols are products that contain therapeutically active ingredients which are packed under pressure and are previously released upon activation of an appropriate actuator and valve system. Aerosols dosage forms can be topically, orally, nasally, and systemically inhaled.

Introduction

The aerosol process containers which are referred to as a pressurised package in which the therapeutically active drug is dissolved or suspended in compressed or liquefied gas. The delivery of therapeutically active drug in the form of spray or foam or solid stream is dependent on the ability of the liquefied or compressed gas.

Advantages of Pharmaceutical Aerosols

 There are some advantages which are related to the use of aerosols which includes: Protection of the drug sensitivity to the effect of oxygen or moisture thus enhancing stability, the drug can be directly applied to the affected areas, administration of drug by aerosol is a rapid process, it protects the drug from gastrointestinal tract degradation, hepatic first pass metabolism is avoided, they are used for both systemic and local application, are easy to apply, sterile dose of drug is dispensed and contamination of drug is prevented.

Features and components of pharmaceutical aerosol  

The delivery of contents of aerosol is dependent on a few features of the container which includes the valve assembly, containers, and actuators as well as on the propellant. 
The components of pharmaceutical aerosols are product concentrate and propellant. The product concentrate contains the therapeutically active ingredients. The propellant having vapour pressure greater than atmospheric pressure at 40°C (105°F) is responsible for the development of proper pressure in the container to expel the product concentrate in the desired form like spray, mist, solid, foam, stream etc. The propellant can also act as the solvent or vehicle for the product concentrate.

A. Propellant

The pressure development within the container of an aerosol by the propellant causes the opening of valve which expels the product by atomisation or foam formation. There are different types of aerosols which is essentially dependent on the route of administration and use. They include: Chlorofluorocarbon (CFC) propellants, hydrocarbon propellants and compressed gas propellants.The basic characteristics of propellants are chemical inertness, lack of toxicity, lack of flammability and explosiveness. 

1. Containers 
   Aerosol containers are generally made of glass, metals (e.g., tin plated steel, aluminium, and stainless steel), and plastics. The materials of pharmaceutical aerosol containers which are to be selected should be able to withstand high pressure. Thus must withstand pressure as high as 140 to 180 psig (pounds per sq. inch gauge) at 130°F. Also, the compatibility of the material of the container with the formulation is to be considered. The brittleness of glass limits its use in aerosol containers. Thus glass containers are used in lower pressure and when low amount of propellant are in use such as if the pressure is less than 25 psig and propellant content is less than 15%. The glass is to be coated with plastic coating in two layers in order to protect the glass containers against breakage due to high pressure. Epoxy and vinyl resins can be used as linings for aerosol containers. Vinyl resins are not resistant to high temperature of the steam about 200°F. But epoxy resins are resistant to steam. These coatings are suitable for low pH water based products. 

Tin plated steel provides light and inexpensive aerosol container. The both sides of the tin container are electroplated with sheets of steel plates so as to protect the inside of the container from corrosion and also to prevent the interaction between the tin and the formulation. 

1. VALVE 

It delivers the drug in desired form and regulates the flow of product concentrate from the container. It should be able to withstand the pressure encountered by the product concentrate and the container, it should be corrosion resistant. The two types of valves available are continuous spray valve and metering valve.
D. ACTUATOR 
This is the button which the users press to activate the valve assembly and controls the easy opening and closing of valve; also directs the spray to the desired area. The actuator contains orifices of varying size and shapes as well as the expansion chamber which determines the type and quantity of products expelled.

Types of Aerosol Systems

Pharmaceutical aerosol systems are classified as: 

1. Solution system or two phase system
   It is also called two-phase system as it contains both the vapour and the liquid. Based on the desired spray, the propellant can be used single or a mixture of propellants can be used. Propellant is added alone or in mixture. If propellants having vapour pressure lower than propellant is added to propellant a reduction of vapour pressure is achieved but bigger sized aerosol particles are obtained. Also bigger sized aerosol particles are obtained on addition of cosolvents like ethyl acetate, propylene glycol, ethyl alcohol, glycerine and acetone. No other solvent is required if the drug is soluble in the propellant. The solution system is administered in topical application.
2. Water based system or three phase system
   The water based or three phase system contains large quantity of water to solubilise the contents. The water is immiscible with the propellant. Generally water based system is a three phase system consisting of a water phase, vapour phase and the propellant. So, the solubility of propellant in water can be increased by adding a co-solvent such as ethanol and also by adding surfactants at a range of composition 0.5% to 2.0 %. The propellant composition ranges from 25 to 60%. The non-polar surfactants such as esters of Oleic acid, palmitic acid, stearic acids are more preferred than the polar surfactants. The surfactants act by reducing the interfacial tension existing between the water phase and the propellant and therefore producing a uniform dispersion by increasing the solubility of the propellant in the water. The disadvantage associated with water based system is that the addition of ethanol not only increases the solubility of propellant in water but also increases its flammability. The presence of large quantities of water delivers content in liquefied form.
3. Foam system: In this system the liquefied propellant is emulsified. It’s ingredients include aqueous or nonaqueous vehicles, propellant and the surfactants are its ingredients. Foam system can also be classified as aqueous stable, nonaqueous stable and the quick breaking foam.

Quality control tests for pharmaceutical aerosols

In pharmaceutical aerosols, its in-process quality control (IPQC) and finished product quality control (FPQC) must be maintained under demanding quality control tests to ensure proper active ingredients and pressurized package performance along with safety during use and storage.
The total quality of the product is assured by the IPQC and FPQC tests. This total quality assurance–dealing process (IPQC and FPQC tests) represents rigorous tests to allow products being completely indefectible before they are launched into the market. Many concerns need to be measured in order to obtain a product with appropriate quality depending on the requirements of the national authorities and legislation, and the manufacturers’ internal policies for production process (safety, marketing, etc.). Quality-control tests and standard guiding principles for pharmaceutical aerosols are obtained from pharmacopeias and regulative associations such as British Pharmacopoeia, United States Pharmacopoeia, National Formulary (USP-NF), International Pharmacopoeia, the international pharmaceutical aerosol consortium on regulation and science association, and the EPAG.The purpose of IPQC is the monitoring and assessment of the quality of pharmaceutical products’ evaluation and carry on necessary production adaptation for the manufacturing process to comply with pharmacopeias. FPQC tests are performed with the purpose of evaluating qualitative and quantitative features of the finished product as well as asses test procedures and their acceptance parameters, that should obey by the finished pharmaceutical product throughout its valid shelf life.

1. Spray test

 The main purpose of this quality control test is to eliminate any pure propellant from the dip tube as well as any concentrate and to inspect for defects in valves and spray patterns. This test method encompasses the impingement of test sprays on the surface of a treated piece of paper with a dye-talc mixture. The nature of the aerosol determines whether a water-soluble or oil-soluble dye is to be applied. The sprayed particles that strike on the surface of the substrate testing paper cause the dye to be converted into solution and to be absorbed onto the paper. The outcome of this test gives a highlighted result that the spray design can be used for comparative assessment of spray pattern. For metered dose aerosols, the spray pattern of a pharmaceutical aerosol can have a great effect on the dose of the medication that reaches the patient’s lungs.

2. Leak test

 This  test is done by checking the crimping of the aerosol dispenser valve which must be available to avoid defective containers. This is accomplished by determining the crimp’s measurements and ensuring that their dimensions meet specifications. This evaluating test involves allowing the filled containers passing through a water bath and final testing of valve closure is done. 

3. Weight check 

 This testing procedure investigates the accuracy of the filling procedure and assurance of uniformity of the final total weight of the product. Tis test is carried out by periodical addition of empty aerosol container to filling lines which is removed later after being filled with the product concentrate and weighed and usually repeated to check the weight of the propellants. As a further assessment, the finished product filled container is weighed to check the accuracy of the filling operation.

4. Valve acceptance

 This test is ensures that the valves are procured from technically acceptable sources. This is done through testing of a valve to its design limits of temperature and pressure. The valve acceptance test procedure applies to two categories of metered aerosol valves are employed which includes Deliveries 54 µL or less (limit’s ±15%), deliveries 55–200 µL (limit’s ±10%). Any value obtained during testing outside of this value is considered not up to quality.

5. Propellants test 

 This test is performed to identify the composition of the mixture existing when a blend of the propellants is applied, and see whether or not it matches the label. It is carried out using IR spectrophotometry or gas chromatography. It is inspected for the vapor pressure to determine its moisture content, density, nonvolatile residue, and halogen determination as signs of purity and to ensure it is a quality propellant.
Pharmaceutical aerosols should be tested and evaluated in order to ensure that they have satisfactory performance and appropriate safety while being packaged, stored, and used. Thus certain biological, physical, and chemical parameters should be tested and evaluated on aerosols—these tests will be discussed in further details in this section.

6. Flammability and combustibility

Based on the type and amount of the ingredients, certain pharmaceutical aerosols contain flammable propellants such as hydrocarbon propellants. In order to guarantee the safety of such products prior to patient use, storage and transportation. The flammability and combustibility of  pharmaceutical aerosols should be evaluated. Flammability and combustibility can be determined through the upcoming procedures:

1. Flash point: This the temperature that measures the propensity of the test concentrate sample to form a flammable blend with air under controlled defined laboratory conditions. This is useful in determining correct conditions for storage, shipping, and to state safety regulations for flammable and combustible materials. Flash point test protocol is done by cooling the temperature of the aerosol product to almost 25°F, then the aerosol is captive to the testing apparatus. Gradually start to increase the temperature of the test liquid; the lowest temperature at which the vapor will ignite is recorded and this temperature is known as the flash point. 
2. Flash extension and flashback: This type of evaluation test is also known as the flame projection test. The aerosol is sprayed through an open candle flame for about 4 seconds at a fixed distance of 6 in. (15 cm), using a suitable ruler the flame’s extension is measured in (cm) and the length of the flame projection is recorded. An aerosol product is judged flammable if its flame extends 18 in. (46 cm) or more through an open flame, or if the flame flashes back to the actuator. The extension of the flame is reliant on the ingredient’s nature of the aerosol’s preparations.

7. Therapeutic activity

The testing of the therapeutic activity of aerosols is associated with the particle size spreading. As a primary step, the dosage of the inhaled aerosol must be determined surely prior to testing the therapeutic activity of inhaled aerosol. For topical aerosols, therapeutic activity is determined by topically applying the therapeutically active ingredients directly to the test areas and evaluating the amount of therapeutically active substances absorbed.

8. Physicochemical characteristics

The chemical and physical characteristics of pharmaceutical aerosols determine their atmospheric removal by gravitational force, diffusion and extent of water absorption which leads to increase in size and subsequent elimination by both wet and dry deposition. The basic chemical and physical properties of aerosols includes:

1. Measurement of Vapor pressure and total Vapor Pressure: This can be achieved with the use of special equipment such as a pressure gauge, water bath, test gauge. Determining pressure indicates whether air is present within the dispenser headspace which could affect the stability of the product. To measure vapor pressure accurately a puncturing device can be used. 
2. Density: Using hydrometer or a pycnometer, the relative density of aerosol liquids can be determined. First of all a choke valve, a glass pressure tube, and a metal flanges are fitted all together permitting liquids under pressure to be introduced, then the hydrometer is positioned within the glass pressure tube and the sample is introduced by the valve. This will cause the rising of the hydrometer halfway the tube’s length, and directly the density can be read.
3. Moisture content:  With the use of Chromatography and Karl Fischer methods moisture content of pharmaceutical aerosol are evaluated. 

9. Toxicity test

For Topical Aerosols, the topically administered aerosols are checked for chilling effect or irritation in the skin. When pharmaceutical aerosols are topically applied, thermistor probe attached to the recording thermometer are used to determine the change in skin temperature for a given period of time. For Inhalation Aerosols, toxicity study is done by spraying vapours from the aerosol container on the surface of the nose and skin checked for irritations.

CONCLUSIONS 

Pharmaceutical aerosol is a noninvasive pulmonary drug delivery system which is considered to be one of the best methods as compared to other routes of drug administration. Its advantages over the other route of administration enhance its wide range of application in the treatment of illness. It’s major advantage is the rapid onset of action hence it is important to ensure adequate quality control measures are undertaken for a finished product to ensure safety for transport and use.

REFERENCES 

1. Akira T., Henry F.S., Butler J.P. Particle transport and deposition: basic physics of particle kinetics. Compr. Physiol. 2013;3(4):1437–1471. [PMC free article] [PubMed] [Google Scholar]
2. Apiou-Sbirlea G., Newman S., Fleming J., Siekmeier R., Ehrmann S., Scheuch G. Bioequivalence of inhaled drugs: fundamentals, challenges and perspectives. Ther. Deliv. 2013;4(3):343–367. [PubMed] [Google Scholar]
3. Ashurst I., Malton A., Prime D., Sumby B. Latest advances in the development of dry powder inhalers. Pharm. Sci. Technol. Today. 2000;3(7):246–256. [PubMed] [Google Scholar]
4. Aulton M., Taylor K. The Design and Manufacture of Medicines. fourth ed. Churchill Livingstone; 2013. eBook. [Google Scholar]
5. Azarmi S., Lobenberg R., Roa W.H., Tai S., Finlay W.H. Formulation and in vivo evaluation of effervescent inhalable carrier particles for pulmonary delivery of nanoparticles. Drug Dev. Ind. Pharm. 2008;34(9):943–947. [PubMed] [Google Scholar]
6. Borghardt J.M., Kloft C., Sharma A. Inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes. Can. Respir. J. 2018;2018 doi: 10.1155/2018/2732017. Article ID 2732017, 11 pages. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
7. British Pharmacopoeia Commission, 2014. British Pharmacopoeia, eighth ed. Stationery Office, Great Britain.
8. Carvalho T., Peters J., Williams R. Influence of Particle Size on Regional Lung Deposition-What Evidence is There? Int. J. Pharm. 2011;v.406(no.1-2):1–10. (ISSN: 0378-5173) [PubMed] [Google Scholar]
9. Chantal D., Kim Prisk G. Aerosol deposition in the human respiratory tract breathing air and 80:20 Heliox. J. Aerosol Med. 2004;17(3):278–285. 2004. [PMC free article] [PubMed] [Google Scholar]
10. Chen M.-L., Shah V., Patnaik R., Adams W., Hussain A., Conner D. Bioavailability and bioequivalence: an FDA regulatory overview. Pharm. Res. 2001;18(12):1645–1650. [PubMed] [Google Scholar]
11. Lachman L, Lieberman HA, Kanic JL editors. The theory and practice of industrial pharmacy. 3rdEdition. India: Varghese publishing house; 1976. p 589-618.
12. SciarraJJ, Sciarra CJ. Aerosols. In: Remington, The science and practice of pharmacy. 21stedition. India: Lippincott Williams and Wilkins; 2005.p 1000 –1017.
13. BankerGS, Rhodes C editors.Modern Pharmaceutics. 4thedition. New York: CRC press; 2006.p718-745.
14. ChanHK, Chew NYK. Dry powder aerosols: Emerging Technologies. In: Swarbick J editor. Encyclopedia of pharmaceutical technology. 3rdEdition. New York: informa healthcare; p 1428-1434.
15. Aulton ME, Editor. Pharmaceutics –The science of dosage form design. New York: Churchill Livingstone; p 473-488.6.Pokar HG, Patel KR, Patel NM. Review on: Pharmaceutical aerosol. Internationale Pharmaceutica Sciencia 2012; 2(2): 58-66.