Suspensions physical stability

All povidone types can be used as hydrophilic polymers to physically stabilize suspensions [39,119]. Their most important and primary function in all suspensions is as protective colloids, which hydrophilize the individual solid particles and sterically separate them. This increases the volume of any sediment and makes it easier to redisperse by shaking. Povidone also prevents the dissolved portion of the active substance from crystallizing out by forming soluble complexes with it [389] (see also Sections 2.2.7 and 2.4.5). The Zeta potential of many substances, e. g. iron oxide pigments, can also be reduced with povidone [421]. 

Generally, the physical stability of a pharmaceutical suspension can be appropriately adjusted by an alteration in the dispersed phase rather than by significant modifications in the dispersion medium. These adjustments are mainly concerned with particle size, uniformity of particle size, and separation of the particles so that they are not likely to become larger or to form a solid cake upon standing. 

RDC Jones, BA Matthews, CT Rhodes. Physical stability of sulfaguanidine suspensions. J Pharm Sci 59 518-520, 1970. 

GC Na, HJ Stevens, BO Yuan, N Rajagopalan. Physical stability of ethyl diatrizoate nanocrystalline suspension in steam sterilization. Pharm Res 16(4) 569-574, 1999. 

Studies of polymorphs in recent years have pointed out the effects of polymorphism on solubility and, more specifically, on dissolution rates. The aspect of polymorphism that is of particular concern to the parenteral formulator is physical stability of the product [8]. Substances that form polymorphs must be evaluated so that the form used is stable in a particular solvent system. Physical stresses that occur during suspension manufacture may also give rise to changes in crystal form [9]. 

Sterile suspensions can be challenging with respect to physical stability, and this should be reflected in the... 

Pharmaceutical scientists have developed improved suspension dosage forms to overcome problems of poor physical stability and patient-perceived discomfort attributed to some active ingredients. An important development aspect of any suspension is the ability to resuspend easily any settled particles prior to instillation in the eye and ensure that a uniform dose is delivered. It would be ideal to formulate a suspension that does not settle since the patient may not always follow the labeled instructions to shake well before using. However, this is usually not feasible or desirable since the viscosity required to retard settling of the insoluble particles completely would likely be excessive for a liquid eyedrop. The opposite extreme, of allowing complete settling between doses, usually leads to a dense layer of agglomerated particles that are difficult to resuspend. 

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

Investigations of the rheological properties of disperse systems are very important both from the fundamental and applied points of view (1-5). For example, the non-Newtonian and viscoelastic behaviour of concentrated dispersions may be related to the interaction forces between the dispersed particles (6-9). On the other hand, such studies are of vital practical importance, as, for example, in the assessment and prediction of the longterm physical stability of suspensions (5). 

The most important parameters for the physical stability of suspensions are the relative volume of sediment (= volume of sediment/total volume) and the redispersability. They are tested after 1 -4 weeks have elapsed. 

Clements and Popli (1973) summarized transformation times during dissolution of pharmaceutical compounds from the literature. Theirstudy with meprobamate found that it took 168 h to convert to form I. Other than the example of chloramphenicol palmitate, this was much longer than most systems, which converted to the stable modiLcation in 300 s (theophylline) to 24 h (ampicillin). This is generally slow enough to allow therapeutic advantages to dosing the metastable solid orally, but too rapid to market suspensions of these forms with adequate physical stability. 

In most cases, physical instabilities are consequences of previous chemical instabilities. Physical instabilities can arise principally from changes in uniformity of suspensions or emulsions, difficulties related to dissolution of ingredients, and volume changes [6], For instance, some cases where physical stability has been affected are cloudiness, flocculence, film formation, separation of phases, precipitation, crystal formation, droplets of fog forming on the inside of container, and swelling of the container [8],... 

There are some useful methods to improve the physical stability of a suspension, such as decreasing the salt concentration, addition of additives to regulate the osmolarity, as well as changes in excipient concentrations, unit operations in the process, origin and synthesis of the drug substance, polymorphic behavior of the drug substance crystals, and other particle characteristics. However, methods based on changes of the particle properties and the surfactants used are the most successful [43],... 

To approach physical stability problems of suspensions, effectiveness and stability of surfactants as well as salt concentrations must be checked with accelerated aging. In addition, unit operations affecting particle size distribution, surface area, and surfactant effectiveness should be approached, taking into account that different types of distributions, for instance, volume or number weighted, give a different average diameter for an equal sample [43],... 

Keeping the particles uniformly distributed throughout the dispersion is an important aspect of physical stability in suspensions. Based on Stokes s law for dilute suspensions where the particles do not interfere with one another, there are different factors that control the velocity of particle sedimentation in a suspension, for instance, particle diameter, densities of the dispersed phase and the dispersion medium, as well as viscosity of the dispersion medium [36]. Remington describes the formulation of trisulfapyrimidines oral suspension [1], In addition, Lieberman et al. [42,48] are also good sources of typical formulations for suspensions. 

Gg (instantaneous modulus), Hg (residual viscosity) and G (shear modulus) all showed a rapid increase above 30g dm bentonite. This was attributed to the formation of a gel network structure in the continuous medium and the strength of such a gel increased with increase in bentonite concentration. The results could be qualitatively described in terms of the elastic floe model of Hunter and co-workers. Moreover, the settling characteristics of the structured suspensions were found to be consistent with the predictions from the rheological measurements. This demonstrates the value of rheological studies in predicting the longterm physical stability of suspension concentrates. 

Physical Stability of Drug Suspension. The physical stability of the non-polar drug suspensions formulated in pMDIs again depends on many parameters, such as propellant type, chemical properties of the drug compounds, and the surfactants used in the formulation. A suspension is a liquid system in which insoluble solid particles are dispersed in a liquid medium. Suspensions can be divided into colloidal suspensions, in which the... 

Sedimentation ratio is often used to assess suspension stability. Byron reported the sedimentation ratios for a 1% sodium fluoresein suspension formulation with different amounts of surfactant (sorbitan trioleate) after standing for 20 days at room temperature. The suspension formulation with the lowest sedimentation ratio had thebest-flocculated system. However, all formulations were easily redispersible one complete revolution of the container was sufficient to produce a homogeneous dispersion. There was no clear difference in the times taken to reach apparent sedimentation equilibrium. Physical stability of the formulation was determined according to ... 

Powder color, texture, particle size, fill weight, smell, case of reconstitution, reconstitution volume, viscosity, taste, color stability after reconstitution, and physical stability of suspension are critical blinding parameters. 

Tingstad reviewed test methods for determining the physical stability of pharmaceutical suspensions. The procedures outlined are designed to determine the state of flocculation of a formulation. Because there is more than one method of preparing stable suspensions, the following test methods and performance criteria were found useful for determining the stability of both flocculated and dispersed systems. 

The pH value of aqueous suspensions should be taken at a given temperature and only after settling equilibrium has been reached, to minimize pH drift and electrode surface coating with suspended particles. Electrolyte should not be added to the external phase of the suspension to stabilize the pH, because neutral electrolytes disturb the physical stability of the suspension. 

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