Quality attributes

Quality attributes

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 separa-tion of the dispersed phase from the dispersion medium. The propor-tion 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 hydro-philic polymers can inhibit or minimize crystal growth by adsorption on the surface of dispersed particles. For example, polyvinylpyrrol-idone (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 dis-pensing conditions by a patient. Deliverability is a function of vis-cosity 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 bot-tle 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 paren-teral, 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 per-ception 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. Surfactants can modify the adhesion of suspension particles by decreasing surface tension and adsorption on the particle surface, leading to modifica-tion forces of interaction between the suspended particles and the container.

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 proper-ties, 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 deg-radation 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 biologi-cal fluids at the site of absorption on administration. Since suspen-sion 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.

In addition, there are special requirements for suspensions depending on their specific usage. For example, suspensions for external use, such as lotions should be fluid enough to spread easily but not so fluid that it runs off the surface too quickly. They must dry quickly and provide an elastic film that will not rub off easily. They must also have pleasant color and odor, although sweetener is not needed.

The quality attributes of a suspension reconstituted from a PFS are same as those of a suspension that is marketed in a ready-to-use form. In addi-tion, there are quality requirements for the unit dose PFS powder sachets or the multidose PFS powder in a bottle. For example:

1.        Fill amount: The amount of powder per container must be tightly controlled to be as close as possible to the amount listed on the label. For a unit dose container, the dispensable or deliverable amount, in addition to the label amount, is measured.

2.        Reconstitution time: As PFS are meant for reconstitution by the patient or the pharmacist, the suspension should be readily formed on addition of water and reasonable manual agitation.

3.        Uniformity of content: Container-to-container uniformity of content of the PFS is important to assure uniformity of the drug amount dis-pensed across different containers.

4.        Physical and chemical stability: The PFS must maintain physical and chemical stability throughout the labeled shelf life under the labeled storage conditions.