Quality attributes of suspensions include the following:
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.
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