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Table of Contents 1. Introduction 2. Reasons for the Pharmaceutical Suspensions 3. Classification of the Pharmaceutical Suspensions 4. Features of an Ideal Suspension 5. Important factors to be considered in formulation of the Suspensions 6. Aerosols 7. Advantages of the aerosols 8. Pharmaceutical Aerosols 9. Meter-dosed Inhaler (MDI) 10.Proper administration and usage of the aerosol 11. Summary 12.References
INTRODUCTION Dispersed systems consist of two phase: the substance that is dispersed known as the dispersed (or) internal phase and a continuous (or) external phase. Based on the particle size of the dispersed phase, dispersion are generally classifies as molecular dispersion, colloidal dispersion and coarse dispersion. Suspensions are the class of dispersed system in which a finely divided solid is dispersed uniformly in a liquid dispersion medium. When one or more type of solid particles that constitute the internal phase are pharmaceutically useful and there therapeutically active the suspensions is known as pharmaceutical suspensions (Herbert A. Lieberman, 1996).
REASONS FOR SUSPENSIONS
There are several reasons for preparing suspensions ((Loyd V. Allen Jr., 2010) & (Alok K. Kulshreshtha, 2009)): Certain drugs are chemically unstable in solution but stable when suspended. In this instance, the suspension ensures chemical stability while permitting liquid therapy. For many patients, the liquid form is preferred to the solid form of the same drug because of the ease of swallowing liquids and the flexibility in administration of a range of doses. This is particularly advantageous for infants, children, and the elderly. To overcome the instability of certain drug in aqueous solution: o Insoluble derivative formulated as suspension An example is ox tetracycline HCL calcium salt (Instable) (Stable) o Reduce the contact time between solid drug particles and dispersion media increase the stability of drug like Ampicillin by making it as reconstituted powder. o A drug that degraded in the presence of water suspended in non-aqueous vehicles. Examples are phenoxymethypencillin/ coconut oil and tetracycline HCL/ oil The disadvantage of a disagreeable taste of certain drugs in solution form is overcome when the drug is administered as undissolved particles of an oral suspension. In fact, chemical forms of certain poor-tasting drugs have been specifically developed for their insolubility in a desired vehicle for the sole purpose of preparing a palatable liquid dosage form. For example, erythromycin estolate is a less water-soluble ester form of erythromycin and is used to prepare a palatable liquid dosage form of erythromycin, the result being Erythromycin Estolate Oral Suspension, USP. Use of insoluble forms of drugs in suspensions greatly reduces the difficult taste-masking problems of developmental pharmacists, and selection of the flavorants to be used in a given suspension may be based on taste preference rather than on a particular flavorants ability to mask an unpleasant taste. For the most part, oral suspensions are aqueous preparations with the vehicle flavored and sweetened to suit the anticipated taste preferences of the intended patient.
CLASSIFICATION OF SUSPENSIONS
Suspensions can be classifies based on the characteristics of the dispersed phase or the dispersion medium (Ram I. Mahato, 2007) Based on the particle size of the dispersed phase: Coarse Suspensions: Suspensions with the particle size greater than 1m. Colloidal Suspension: Suspensions with the particle size below 1m Nano Suspensions: Suspensions with the particle size 10-100 nm
Based on the routes of administration: Suspensions as drug dosage forms can be prepared for oral, topical, ophthalmic, otic, and nasal route of administration. These are briefly described as follows (Leon Lachman, 1986): Oral Suspensions: Suspensions meant for peroral route of administrations (in which the drug is swallowed and enters the systemic circulation primarily through the membranes of the small intestine) are usually liquid preparations in which solid particles of the active drugs are dispersed in a sweetened, flavored and usually. For example, amoxicillin oral suspension contains 125-500 mg/5ml of suspension.
are designed for dermatologic, cosmetic, and protective purposes. For example topical suspension Calamine lotion USP, contains 118ml of suspension.
Source : http://newbuy.ca/antiseptic-ointments/95-swan-calamine-topical-suspension-usp-118ml.html
Injected Suspensions: Parental suspensions may contain from 0.5% to 30% of solid particles. Viscosity and particle size are significant factors because they affect the ease of injection and the availability of the drug in the therapy. Most parenteral suspensions are designed for intramuscular or subcutaneous administration. For example, procaine penicillin G suspension is intended for the intramuscular administration.
Source: http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=15447
Rectal suspensions: These are exemplified by the anti-inflammatory 5-acetyl salicylic acid (5ASA) rectal suspension enema for ulcerative colitis.
Source : http://www.drugs.com/pro/mesalamine-rectal-suspension.html
Liposomes and micro-/nano-particles: Suspensions of liposomes, microspheres, microcapsules, nanospheres and nanocapsules are formed from a variety of polymers or proteins. These suspensions formulations are used for targeted and controlled delivery of drugs.
Several drug delivery systems using liposomes such as Doxil and Daunome are in market.
Source : http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=53683
Otic Suspensions: These ate intended for administration into ear. Most otic suspensions are antibiotics for the treatment of ear infections and may also be corticosteroids for minimizing inflammation and analgesics for pain relief. and hydrocortisone for antibiotic and anti-inflammatory effect Based on the type of the dispersed system Aqueous suspensions Nonaqueous suspensions: Although most pharmaceutical suspensions have primarily aqueous
continuous phase, formulation of a drug in a nonaqueous continuous phase, is occasionally required. Suspensions of a water-soluble drug in a nonaqueous vehicle may provide a means to prepare a liquid formulation of a drug that has poor long-term stability in aqueous solution. Aerosols represent important class of nonaqueous suspensions. The physical stability of suspended drugs in non-aqueous propellants for aerosols products can have a significant impact on the uniformity of dose and operation of the aerosol system.
FEAUTRES OF AN IDEAL SUSPENSION In contrast to the formulations of the liquid dosage form such as solutions and solid dosage forms such as tablets and capsules, the development and preparation of the suspensions dosage form involves a great challenge. Pharmaceutical formulations are thermodynamically unstable. Formulation of such suspension is difficult because often these systems faces the problems of physical stability, content uniformity, sedimentation, caking, redispersion and crystal growth. Moreover, in formulating the pharmaceutical suspension factors such as palatable for improving the taste and undesirable odor of the drug is also taken into consideration. Following are some desired attributes of a perfect and elegant pharmaceutical suspension (Alok K. Kulshreshtha, 2009)& (Ram I. Mahato, 2007): 1. For a given batch of the suspension the content of drug should remain uniform from one package to another. 2. For every dose released from the container, the quantity of drug dispensed should remain consistent. 3. Physical attributes such as particle size, PSD, viscosity should remain nearly uniform throughout the shell life of the product. 4. Suspended material should settle slowly and should readily dispersed upon gentle shaking of the container such as it uniformity is maintained with each dose. 5. Particles having lower settling velocity tends to form a hard cake. In an ideal suspension, these should never happen, but those particles should be readily redispersed upon the shaking. 6. Suspension viscosity should be such that, it should pour freely form the bottle or to flow through a needle syringe (for injectable suspension) or spreads freely on the affected area (for topical suspension). 7. There should be no microbial growth. 8. The suspension should not show any unexpected change in color or any other change in physical appearance or odor. 9. The suspension should be chemically stable, it should not degrade during the shell life and storage.
10. The drug must not recrystallize and/or change its polymorphic form during the storage of the formulation. These main features of a suspension, which depend on the nature of the dispersed phase, the dispersion medium, sedimentations rate, viscosity and various others factors. And all the factors that are to be given a due consideration in order to attain the desired features are described briefly next.
IMPORTANT FACTORS TO BE CONSIDERED IN FORMULATION OF THE SUSPENSION There are many considerations in the development and preparation of a pharmaceutically elegant suspension. (Loyd V. Allen Jr., 2010). Selection of the API and excipients for the formulation of the suspension should be selected carefully depending on the route of administration, end application, and possible adverse effects. The following are the most important factors to be considered during the formulation of pharmaceutical suspensions (Alok K. Kulshreshtha, 2009): 1. Nature of suspended material: Among all the properties of the suspended material, the important consideration should be given to the interfacial properties during the formulations of a suspension. Material having low interfacial tension exhibits good wetting property and readily gets suspended. In contrast, the materials possessing high interfacial tensions are not easily wetted. For such materials, suspensions is aided by using surfactants. Surfactants increase wettability of the particles by reducing their surface tension. The main function of wetting agents: (1) to reduce the contact angle between surface of solid particles and wetting liquid via displace the air in the voids (2) surfactant. Excessive amounts of wetting agents can cause foaming or undesirable taste or odor. 2. Size of suspended particles: Particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study. Too large or too small particles should be avoided. Larger particles will settle faster at the bottom of the container and too fine particles will easily form hard cake at the bottom of the container. The particle size can be reduced by using mortar and pastel but in large-scale preparation different milling and pulverization equipments are used. Limitation in particle size reduction (after reaching a certain particle size): Expensive and time consuming Movement of small particles due to Brownian motion cause particles to aggregate, settle, form hard cake that it is difficult to redispersed
3. Viscosity: For the suspension to be highly viscous, it is necessary that it possess the property of shear thinning. The advantage of high viscous dispersion medium is that it has lower sedimentation rate. The viscosity of the media also affects the velocity of sedimentation. It decreases as the viscosity of the vehicle increases. The viscosity and
density of any vehicle are related to each other, so any attempt to change one of these parameters will also change the other one.
AEROSOLS Pharmaceutical aerosols are pressurized dosage forms that upon actuation emit a fine dispersion of liquid and/or solid materials containing one or more active ingredients in a gaseous medium (ansel). Aerosols consists of the gas that may be condensed or liquefied and it has ability to bring out the API and other ingredients out of the compartment. Pharmaceutical aerosols are like other dose structures since they require the same sorts of contemplations regarding definition, item solidness, and helpful viability. On the other hand, they vary from most other dosage form in their reliance upon the capacity of the compartment, its valve assembly, including the propellant- for the physical release of the medicine in suitable form. (ansel). The presence of propellant generates the pressure inside the package. Upon the actuation of the valve, this pressure forces the ingredients in the package to expel out through the opening in the valve (Loyd V. Allen Jr., 2010). An aerosol formulation essentially consists of two components: 1. Product concentrate 2. Propellant. Aerosols generally contain an active drug in a liquid gas propellant, in a mixture of solvents with a propellant, or in a mixture with other additives and a propellant. The concentrate can be a solution, suspension, emulsion, semisolid, or powder. The force that is required to eject the product concentrate from the compartment is imparted by the propellant. Moreover, propellant is also responsible for the delivery of the formulation in the proper form (i.e., spray, foam, semisolid). The gas propellants can be formulated to provide desired vapor pressures for enhancing the delivery of the medication through the valve and actuator in accordance with the purpose of the medication. When the propellant is a liquefied gas or a mixture of liquefied gases, it can also serve as the solvent or vehicle for the product concentrate (Leon Lachman, 1986).
Figure: Components and Operation of Aerosol System (Loyd V. Allen Jr., 2010)
Aerosols are used as space sprays, surface sprays, aerated foams, and for oral inhalation. Aerosols used to provide an airborne mist are termed space sprays. Room disinfectants room deodorizers, and space insecticides characterize this group of aerosols. The particle size of the released product is generally quite small, usually below 50 m, and must be carefully controlled so that the dispersed droplets or particles remain airborne for a long time. Aerosols intended to carry the active drug to a surface are called surface sprays or surface coating sprays. A great many cosmetic and household aerosol products, including personal deodorant sprays, hair lacquers and Figure: Pharmaceutical Aerosol ( (Loyd V. Allen Jr., 2010) sprays, perfumes and colognes, shaving lathers, toothpaste, surface pesticide sprays, paint sprays, spray starch, waxes, polishes, cleaners, and lubricants (Loyd V. Allen Jr., 2010).
1. Aerosols are easy to use. Medication is dispensed at the push of a button. No ancillary equipment is needed. 2. Aerosol application is a clean process which requires minimal patient "clean up" after using the product. 3. A portion of medication may be easily withdrawn without contaminating the remaining material. If the product is sterile, sterility can be maintained throughout the product's shelf life. 4. The active drug is protected from oxygen and moisture. The usual aerosol container is opaque which also protects the drug from light. 5. By proper formulation and valve control, the physical form and the particle size of the emitted product may be controlled. 6. If the dosage must be regulated, a metered dose valve can be used which will control the accuracy of the administered dose. 7. Aerosol application is a clean process, requiring little or no washup by the user.
PHARMACEUTICAL AEROSOL APPLICATIONS Pharmaceutical aerosols have been playing a crucial role in the health and wellbeing of millions of people throughout the world for many years. These devices includes: metered-dose inhalers (MDIs) dry powder inhalers (DPIs) nebulizers These devices deliver a specific quantity of drug to the lungs. For the inhalation aerosols, the particle size distribution and shape of the delivered dose is more critical than for most other conventional drug products because these factors greatly influence the deposition profile in the lungs of the patient. The optimum aerodynamic particle size distribution for most inhalation aerosols has generally been recognized as being in the range of 1-5 m (Loyd V. Allen Jr., 2010).
creating an aerosol containing micronized drug that is inhaled into the lungs. The canister is impenetrable to the ambient conditions when the actuator valve is close and under this position the canister is packed with the formulation. The entire system is reinstated for the next dose upon the release of the actuator. The quantity of the drug released upon the actuation is measured by tests framed by the United States Pharmacopeia. The potential in delivering the medication, its local and systemic effects lies on the particle size of the inhaled drug (Ansel & link). Breathing patterns and the depth of respiration also play important roles in the deposition of inhaled aerosols to the lungs. Analysis of dose uniformity, particle size distribution patterns and the respirable fractions of Aerosol-delivered particles are areas of research in developing aerosol products for optimal oral inhalation therapy (Loyd V. Allen Jr., 2010).
physically and chemically, and maintain the viscosity during the storage and shell life. Therefore, development of the pharmaceutical suspension is very complex process and it is very important to have better understanding of the properties of the both the dispersed phase and continuous phase. The most important factors to be considered during the formulation have been discussed. In the context and limitation of this report only the three main factors particle size, nature of the media and viscosity have been included. Apart from these factors, there are various other factor such as sedimentation rate, charge stabilization, crystal growth, interactions of the components etc. should be thoroughly understood form the stability of the pharmaceutical suspensions. The last part of the report deals with the aerosols, one of the most important form of the nonaqueous suspensions. Aerosols is gaining importance in the pharma industry as aerosol therapy is local, rapid and intense. The inhaled drug goes directly into lungs. Different aspects of the aerosols have been briefly described and emphasis is given on the Metered dose inhaler (MDI) as it is the most common pharmaceutical aerosols. The most common challenge that the scientist is facing is developing more environmentally friendly and safer inhalers. The most common propellant used in the aerosols in the chlorofluorocarbons (CFC) since these have adverse effect on the ozone layer and also being flammable they threat the patient safety too. So, research is going on in find new and safe propellant. Further, this report can be extended to the nanosuspensions. Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs because of their versatile features and unique advantages. Rapid advances have been made in the delivery of nanosuspensions by oral, ocular, parenteral and pulmonary routes. Currently efforts are being made directed to extend their applications in site specific drug delivery (Alok K. Kulshreshtha, 2009). REFERENCES 1. Alok K. Kulshreshtha, O. N. (2009). Pharmaceutical Suspensions: From Formulation Development
to Manufacturing. New-York: Springer. 2. Herbert A. Lieberman, M. M. (1996). Pharmaceutical Dosage forms: Disperse Systems Volume 1. New-York: Marcel Dekker,Inc. 3. Leon Lachman, H. A. (1986). The Theory and Practice of Industrial Pharmacy . Lea & Febiger. 4. Loyd V. Allen Jr., N. G. (2010). Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Lippincott Williams & Wilkins. 5. Ram I. Mahato, A. S. (2007). Pharmaceutical Dosage Forms and Drug Delivery. CRC Press.