Suspension is the dispersion of a solid in a liquid or gas. A pharmaceutical suspension is the dispersion of solid particles (usually a drug) in a liquid medium (usually aqueous) in which the drug is not readily soluble. This dosage form is used for providing a liquid dosage form for insoluble drugs.
The particle size of the dispersed phase in most of the oral pharmaceutical suspensions is between 1 and 50 μm. The lower the particle size, the larger the surface area of the suspended drug. Lower particle size allows the formation of a uniform, fine particle suspension with low grittiness and high redispersibility. A larger surface area of the dispersed drug promotes rapid drug dissolution on dilution with biological fluids upon administration.
In addition to the use of aqueous pharmaceutical suspensions as drug products, suspensions are also used as in-process materials during industrial pharmaceutical manufacturing. For example, tablets are coated with a suspension of insoluble coating materials.In pharmaceutical dispersion (suspensions) the internal (drug) phase will separate upon storage; however, the main aim of the formulation scientist is to control the process of separation and, in so doing, optimize the stability of the formulation. A pharmaceutical suspension would be considered stable if, after agitation (shaking), the drug particles are homogeneously dispersed for a sufficient time to ensure that an accurate dose is removed for administration to the patient.
Types of suspensions
Suspensions can be classified based on the characteristics of the dispersed phase or the dispersion medium, and also based on their route of administration.
Based on the particle size (diameter) of the dispersed phase, suspensions can be classified as (1) coarse suspension (below 1 μm), (2) colloidal dispersion (greater than 1 μm), or (3) nanosuspension (10–100 nm).
Based on the concentration of the dispersed phase, highly concentrated suspensions are termed as slurries (greater than 50% w/w), and certain suspensions are considered dilute suspensions (2%–10% w/w). Based on the type of the dispersion medium, suspensions can be aqueous or non-aqueous. Identifying the physical state of the dispersion medium allows the suspensions to be classified as solid-in-liquid or solid in gas (aerosols) suspensions.
Based on the route of administration, suspensions can be classified as oral, topical, ophthalmic, otic, or nasal suspensions. Each of these present unique challenges and requirements in terms of desired quality attributes. These are briefly described as follows:
1. Oral suspensions: Suspensions meant for per oral route of administration are usually liquid preparations in which solid particles of the active drug are dispersed in a sweetened, flavored, sometimes colored, and usually viscous vehicle.
For example, amoxicillin oral suspension contains 125–500 mg dispersed active pharmaceutical ingredient (API) per 5 mL of suspension. When formulated for use as pediatric drops, concentration of suspended API is increased to allow lower volume of administration for pediatric doses. Antacids and radio-opaque suspensions generally contain high concentrations of dispersed solids.
2. Topical suspensions: Lotions are externally applied suspensions. These are designed for dermatologic, cosmetic, and protective purposes. Topical suspension formulations need to pay particular attention to the lack of grittiness and smooth feel on the skin. These suspensions are typically colored and may have some perfume, but do not need sweeteners and flavors typically used for oral administration.
3. Injectable suspensions: Parenteral suspensions may contain from 0.5% to 30% w/w of solid particles. Viscosity and particle size are significant factors because they affect the ease of injection and the availability of the drug in depot therapy. Most parenteral suspensions are designed for intramuscular or subcutaneous administration. For example, procaine penicillin G suspension is intended for intramuscular administration. Sterility is an important consideration for parenteral suspensions. Being a suspension dosage form, they cannot be sterilized by terminal filtration. Thus, the use of sterile API and aseptic processing is required for their manufacturing. In addition, antimicrobial preservatives are not recommended for intravenous (IV) suspensions.
4. Otic suspensions: These are intended for administration into the ear. Most otic suspensions are antibiotics, corticosteroids, or analgesics for the treatment of ear infection, inflammation, and pain. For example, cortisporin otic suspension contains polymixin, neomycin, and hydrocortisone for antibiotic and anti-inflammatory effect. Otic suspensions are generally formulated as sterile suspensions since they come in contact with the mucosal surface.
5. Rectal suspensions: Local administration through the rectal cavity is used for the treatment or management of local disorders of the colon. For example, 5-acetyl salicylic acid (5-ASA) rectal suspension enema is used as an anti-inflammatory treatment for ulcerative colitis. Formulation and quality considerations for rectal suspensions are similar to the oral suspensions.
6. Aerosols: Aerosols are suspensions of drug particles or drug solution in the air and are used for inhalation of drug delivery to the lung. Volatile propellants are frequently used as vehicles for pharmaceutical aerosols.
7. Liposomes and micro-/nanoparticles: Suspensions of liposomes, microspheres, microcapsules, nanospheres, or nanocapsules are used for targeted and controlled delivery of drugs. These are usually intended for parenteral administration.
8. Vaccines: Vaccines are used for the induction of immunity and are often formulated as suspensions. For example, cholera vaccine and tetanus vaccine are suspensions.
Quality attributes of suspensions include the following:
1. Uniformity of content (dose-to-dose within the same bottle and bottle-to bottle): All the doses dispensed from a given multidose container should have acceptable uniformity of drug content. In addition, the drug content must be uniform between different bottles of a given batch of suspension.
2. Settling volume: Once a suspension has been left undisturbed for a sufficient period of time, it is likely to show some degree of separation of the dispersed phase from the dispersion medium. The proportion of the volume occupied by the separated phase, which contains a higher concentration of the dispersed solid, is an indicator of physical stability of the suspension. Higher this volume, more stable is the suspension. Thus, settling volume is measured as a quality attribute indicative of physical stability of the suspension and its changes over storage stability.
3. Absence of particle size change and active pharmaceutical ingredient crystal growth: Particle size distribution of the suspension should remain fairly constant over time upon storage. Dissolved drug may crystallize or contribute to the growth of existing drug particles.
Crystallization during storage can lead to changes in the particle size distribution of a suspension. Additives in formulation such as hydrophilic polymers can inhibit or minimize crystal growth by adsorption on the surface of dispersed particles. For example, polyvinylpyrrolidone (PVP) can inhibit crystal growth in acetaminophen suspensions.
4. Palatability: Palatability of the dosage form is usually enhanced by the use of sweeteners, flavors, and colorants. For especially bitter or otherwise unpleasant tasting drugs, taste-masking approaches such as drug adsorption on an ion exchange resin may be utilized.
5. Resuspendability: Suspensions are dispensed with the instruction to the patient to shake gently before administration. Suspended material should settle slowly and should readily redisperse upon gentle shaking of the container.
6. Physical stability—absence of caking: Particles that do settle to the bottom of the container should not form a hard cake, but should be readily redispersed into a uniform mixture when shaken. Caking of suspension arises from close packing of sedimented particles, which cannot be eliminated by reduction of particle size or by an increase in the viscosity of the continuous phase. Fine particles have the tendency to cake. Flocculating agents can prevent caking; deflocculating agents increase the tendency to cake.
7. Deliverability: The labeled number of doses and the labeled amount of material should be deliverable from a bottle under the normal dispensing conditions by a patient. Deliverability is a function of viscosity of the suspension. Higher viscosity can lead to more of the suspension sticking to the container, reducing deliverable volume.
8. Flow: Suspensions must not be too viscous to pour freely from a bottle or to flow through a needle syringe (for injectable suspensions). Suspensions are non-Newtonian flowing liquids. Suspensions should be designed as thixotropic or shear-thinning systems rather than shear-thickening systems.
9. Lack of microbial growth: Use of antimicrobial preservatives is deemed sufficient for oral and topical suspensions, whereas parenteral, nasal, and ophthalmic suspensions must be sterile.
10. Physical integrity: The suspension should not show any unexpected change in color, or any other change in physical appearance or perception of the dosage form, such as odor, during storage.
11. Particle adhesion to the package: When the walls of a container are wetted, an adhering layer of suspension particles may build up, and this may subsequently dry to a hard and thick layer. Adhesion often increases with increase in suspension concentration.
12. Polymorphic integrity: Crystallization of the drug could lead to a change in its polymorphic form. A change in the polymorphic form of the drug could lead to changes in its biopharmaceutical properties, such as dissolution rate and absorption. Therefore, the drug must not recrystallize and/or change its polymorphic form during the storage of the formulation.
13. Chemical stability: Refers to a lack of unacceptable chemical degradation of the drug during the shelf life of the product under the recommended packaging and storage conditions. The drug product must meet the predetermined requirements of minimum potency of the API and maximum levels of known and unknown impurities.
14. Drug release: The drug in a suspension must dissolve in the biological fluids at the site of absorption on administration. Since suspension contains the drug in a dispersed, particulate form, the release of the drug into solution in an appropriate dissolution vessel is used as a quality control tool. The rate and extent of drug dissolution must remain consistent throughout the shelf life of a suspension.
Advantages and disadvantages
Advantages of pharmaceutical suspensions
- Pharmaceutical suspensions are a useful drug delivery system for therapeutic agents that have a low solubility. Although low-solubility therapeutic agents may be solubilized and therefore administered as a solution, the volume of the solvent required to perform this may be large. In addition, formulations in which the drug has been solubilized using a co-solvent may exhibit precipitation issues upon storage
- Pharmaceutical suspensions may be formulated to mask the taste of therapeutic agents.
- Pharmaceutical suspensions may be employed to administer drugs to patients who have difficulty swallowing solid-dosage forms.
- Pharmaceutical suspensions may be formulated to provide controlled drug delivery, e.g. as intramuscular injections
Disadvantages of pharmaceutical suspensions
- Pharmaceutical suspensions are fundamentally unstable and therefore require formulation skill to ensure that the physical stability of the formulation is retained over the period of the shelf-life.
- The formulation of aesthetic suspension formulations is difficult.
- Suspension formulations may be bulky and therefore difficult for a patient to carry.