Suspensions physical instability

More subtle effects of preservatives on injectable formulations are possible. Formulation of insulin is an illustrative case study. Insulin is usually formulated as a multiple-dose vial, since individual dosage varies among patients. Preservation of zinc insulin with phenol causes physical instability of the suspension, whereas methyl-paraben does not. However, the presence of phenol is required for obtaining protamine insulin crystals [9]. 

Physical instability of the dosage form tablets that disintegrate too readily creams or suspensions that separate and over- or undercompression of tablets leading to deviation from the required weight... 

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],... 

According to Davies [174], topical ophthalmic suspensions have a number of limitations compared to solutions. They need to be adequately shaken before use to ensure correct dosing, a process which can result in poor patient compliance. In addition, they need to be sterilized, which may cause physical instability of the formulation. Furthermore, the amount of drug required to achieve only a moderate increase in bioavailability is very high, rendering suspensions expensive in terms of their production costs [175],... 

The influence of crystal habit on performance of suspension dosage form can be envisaged to be more pronounced than other dosage forms because of greater space available for reorientation and packing of dispersed particles. Furthermore, selection of a stable habit is essential to avoid crystal growth that leads to physical instability during the shelf life of suspensions. 

Suspensions may also be used to overcome chemical instability of the drug, but at the same time may pose physical instability problems. For example, there may be an increase in particle size with time (Ostwald ripening), or difficulties in resuspension after periods of storage. The latter may result in problems with homogeneity and dose uniformity. The selection of a suitable salt with a low aqueous solubility can be employed to minimise the risk of Ostwald ripening, but it is also important that the suspended particles dissolve reasonably quickly in the eye, or else bioavailability will be reduced. 

A monohydrate phase of metronidazole benzoate exhibited solubility properties different from those of the commercially available anhydrous form [37], The monohydrate was found to be the thermodynamically stable form in water below 38°C. The enthalpy and entropy changes of transition for the conversion of the anhydrate to the monohydrate were determined to be -1200 cal/mol and -3.7 cal/K mol, respectively. This transition was accompanied by a drastic increase in particle size and caused physical instability of oral suspension formula-... 

Dispersed systems such as suspensions can lead to physical instability which can be simply measured by the rate of sedimentation of solids undissolved in the preparation. The formulator should ensure that the suspended material does not settle too rapidly the particles that do settle... 

One of the main requirements of pharmaceutical suspension is the lack of Ost-wald ripening (crystal growth), i.e. the growth of particles on storage that results in shift of particle size distribution to larger values. This may affect bioavailability and results in physical instability. 

In terms of the two-phase system which comprises dispersions of solids in liquids, the minimum energy requirement is met if the total interfacial energy of the system has been minimized. If this requirement has been met, chemically, the fine state of subdivision is the most stable state, and the dispersion will thus avoid changing physically with time, except for the tendency to settle manifest by all dispersions whose phases have different densities. A suspension can be stable and yet undergo sedimentation, if a true equilibrium exists at the solid-liquid interface. If sedimentation were to be cited as evidence of instability, no dispersion would fit the requirements except by accident—e.g., if densities of the phases were identical, or if the dispersed particles were sufficiently small to be buoyed up by Brownian movement. 

Evaluation of the stability/instability of suspensions without any dilution (which can cause significant changes in the stracture of the system) requires carefully designed techniques that should cause as little disturbance to the structure. The most powerful techniques that can be applied in any industrial laboratory are rheological measurements [1-7]. These provide accurate information on the state of the system, such as sedimentation and flocculation, and may also be applied to predict the long-term physical stability of the suspension. The various rheological techniques that can be applied and the measurement procedures are listed below. 

Although a fabric softener is not an emulsion but a suspension of charged particles, it exhibits the same instabilities as an emulsion. The physical stability is twofold phase separation and viscosity. 

A number of case histories are presented in this chapter that illustrate the formulation problems raised by light-sensitive drug substances. These range from the study and formulation of parenteral presentations, in which the product is in solution or suspension form and the instability most closely mirrors that of the drug substance pharmaceutical ointments, in which the drug substance is incorporated as a suspended material in a semisolid base to the physical effects on a tablet formulation where the active is present as solid component. 

Suspension systems of sticky slurry and paste-like liquid explosives with solid particles, based on the dispersion of suspended solid particles, should belong to suspension or coarse multiphase systems in colloid chemistry. In these suspension systems, the main issue is its dynamic instability, because the density of the dispersed particles and the density of the dispersion medium are different (generally, the density particle is greater than that of the medium), settlement or floating can occur with the role of gravitational field to separate the system, resulting in unevenness in composition and density of liquid explosive. Stability is the ability to overcome the so-called sink-and-float separation of two-phase components, therefore, within a certain period of use, the composition and density of explosive and other physical parameters remained unchanged and its properties are stable and reliable. 

The fact that the total number of particles must be conserved during the development of occasional disturbances in a uniform vertical flow or in a homogeneous fluidized bed in itself results in the formation of kinematic waves of constant amplitude, as was first demonstrated by Kynch [48]. Both particle inertia and the nonlinear dependence of the interphase interaction force on the suspension concentration cause an increase in this amplitude. This amounts to the appearance of a resultant flow instability with respect to infinitesimal concentration disturbances and with respect to other mean flow variable disturbances. Various dissipative effects can slow the rate at which instability develops, but cannot actually prevent its development. Therefore, investigating the linear stability of a flow without allowing for interparticle interaction leads inevitably to the conclusion that the flow always is unstable irrespective of its concentration and the physical parameters of its phases. This conclusion contradicts experimental evidence that proves suspension flows of sufficiently small particles in liquids to be hydrodynamically stable in wide concentration intervals [57-59]. Moreover, even flows of large particles in gases may be stable if the concentration is either very low or very high. 

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