PHYSICAL STABILITY TESTING OF DRUGS AND DRUG PRODUCTS
F. THE EMULSION INTERFACE
The factors that stabilize the emulsion system are a layer of surfactant and protective colloid on the exterior of the droplet. The amount of these two must be such that they separate
cover the entire area of the droplets, otherwise coalescence will occur to the extent that the area, A, of the droplets will be reduced to such a point that it now will be completely covered by surfactant and protective colloid. If, for instance, 1 g of emulsion contained Wg of droplets of a size d pm and the oil had a density of p g/cm3, then there would be n droplets per cm3, where n is given ach particle has a surface area of d2, so that the total area is
G. EMULSION TYPE
In emulsion formulation, the type of emulsion is of concern. If it is desired to make an oil-in-water emulsion (olw, i.e., oil is the discontinuous phase), then it is important that phase inversion not occur. Investigating this possibility must be a task in the stability program (and is usually carried out by the formulator, not the preformulator)most often phase inversion is associated with creaming and separation and will be noticed in the appearance testing of the emulsion. Such phenomena lead to graininess of feel. In so e cases part of an emulsion will invert, another not, and then there is a distinct difference in appearances in various regions of the the possibility for inversion should always be considered. It is the more likely the closer the system is to a close-packed system of spheres. In this connection, their of the formulator9s tasks should be to determine the inversion temperature. is is at times used to advantage in the manufacturing step, in that, in producing the emulsion, the inverse emulsion is produced at high temperature; this is then cooled, and at the inversion temperature, the “correct9’ type will result. on version in this manner gives rise to very small globules, and homogenization is then often f an inversion temperature exists, then accelerated testing above . So preliminary testing is always advocated, if accelerated, the philosophy being that there is no sense in testing a system above a temperature where it converts to a physical state that differs from that at room temperature (or recommended storage temperature).
It shown that there is a correction between phase inversion temperature and the rate of coalescence . is possible to use a combination of sedimentation of fractionation and photon correlation spectroscopy to record droplet sizes in fat emulsions, and this would appear to be an excellent technique for studying the coalescence of finer spheres, and hence to obtain an extrapolator tool early on in the storage of an emulsion system.
H. BREAKING AND COALESCENCE
It can be concluded from what has been mentioned that the reasons for breaking would include Chemical incompatibility between the emulsifier and another ingredient in the emulsion system (Borax and gum acacia is a case in point) Improper choice of surfactant pair (e.g., wrong High electrolyte concentration Instability of an emulsifier Too low a viscosity Temperature.
As shown in the foregoing, breaking and creaming of emulsions are the typical defective criteria to be looked for in stability programs. Breaking implies that the emulsion separates into two distinct phases It is a slow process, it often manifests itself in the appearance of small amounts of oil particles on the surface, and it then is referred to as oiling. When separation into two emulsions occurs (as described above), then the phenomenon is called creaming. A rapid test for this is to dip a finger into the preparation and notice if there are different “colors” present rown, 1953). Also, a creamed olw emulsion will not drain off the skin with ease, and the converse holds for a creamed wlo emulsion. A few words regarding the effect of ionic substances and the actual process of flocculation and coalescence are in order. Vanden Tempe1 (1953) demonstrated that flocculation and coalescence are two different processes. Flocculation depends on electrostatic repulsion (and is akin to the zeta-potential considerations discussed previously). Coalescence depends on the properties of the interfacial film.
Cations, as a whole, are less soluble in the oil phase than anions, and this gives rise to negatively charged droplets (akin to the creation of a zeta-potential in suspensions). The potential drop over the film depends on the nature of the electrolyte (and it should be noticed that there is a diffuse double layer in both liquids as opposed to the case of suspensions, where there is only one diffuse double layer).
Electrolytes may either improve or worsen the stability: If they eliminate the protection offered by the surfactant /protective colloid system then coalescence ost often electrolytes have the effect of reducing the emulsifying powers of surfactants and causing salting out or actually precipitating the surfactant. However, in some cases, electrolytes will favorably affect the potential drop over the two double layers, and in this case they may stabilize the suspension system.
4. PHYSICAL STABILITY OF SEMISOLID DOSAGE FORMS
Semisolid emulsions (cold creams, vanishing creams) are not different, in general philosophy, from the above, except that the rheology is checked differently. Davis (1984) has reviewed sophisticated means of checking the stability of these types of systems. He lists the following properties as being important in stability programs for semisolid emulsions:
1. Particle size
2. Polymorphic/ hydration/solvation states
6. Drug release
Of these, particle size, sedimentation/creaming, caking-coalescence, and consistency have been discussed earlier. Following viscosity as a function of time is here of particular interest, The problem is how to measure the viscosity, and what viscosity in essence means. (1987) points out that changes in viscoelastic properties are much more sensitive than simple continuous shear measurements (Barry, 1974). He demonstrates this via data published by Eccleston (1976). Here the variation of the dynamic viscosity (q) and the storage modulus (4) are shown and compared with the same type of graph for apparent viscosity (p’) from continuous shear experiments. It is obvious that the two former measurements are much more sensitive.
The most important concern about transdermals is the release of drug substance from them and the stability of this property. Other properties (stickiness, appearance, etc.) are of importance as well, but the release characteristic is paramount. Kokobo et al. (1991) have described a means of checking this in vivo by using a single diffusion cell. it have reported on the interaction between primitive adhesives and drug combinations used in transdermals. . The data fit neither a diffusion equation (In of retained versus time) nor a square root equation directly. It would appear that if one allows for either an initial dumping in the diffusion equation (or includes more than one term arrear equation) or a lag time in a square root equation, then the data will
B. ACCELERATED TESTING AND PREDICTION
Accelerated testing of physical properties of disperse systems is not as clear-cut as for instance chemical kinetics prediction. For instance, the stability of properties of semisolid materials is very difficult, for instance, for creams and ointments that give rise to bleeding there does not seem to be any reliable predictive test. Yet a series of stress tests are used for disperse systems. They include Shaking tests centrifugal tests Freeze-thaw tests.
For the freeze-thaw test, the question is what the minimum temperature should be, temperatures from -5” to +5”C being the most common. -5°C frequently gives rise to phase separation and irreversible changes that would not be seen in usual temperature ranges (Nakamura and Okada, 1976), but again, such tests may be used to select a “presumably best” formula from a series of preparations in product development. Results of a typical freeze-thaw . centrifugation has been used by some investigators . The general idea is that g can be increased city predicted by Stokes’s law , but often the stresses caused by centrifugation may cause coalescence, which would not occur during nor- mal collision stress. Some investigators claim fair success in predictions by this means, but as avis (1987) cautiously states, “as a general rule it can be stated that systems that accelerated stress conditions should be stable under normal storage con- however the corollary is not necessarily true.” That is, if the preparation fails the test it may still be all right, but if it passes the test it should be all right. although this may be true overall, one can visualize that if a preparation is centrifuged right after manufacture, then the stress does not include the chemical changes (surfactant decomposition for instance) that occur on storage, and in this it may give too optimistic a prediction. usual et al. (1979) have measured phase separation at several different centrifugal gas and have established from these data a so-called coalescence pressure. This (again recalling that the test does not account for chemical changes on storage) may be an appropriate parameter. One predictive method in formulation is the correlation afforded by coalescence rates , and this is rational in selecting the “best,, of many formulations; in general the system with the highest phase inversion temperature is the best. The (nonchemical stability dictated) coalescence rate could theoretically be calculated prior to storage, and the difference between observed and calculated then attributed to chemical stability causes.
For emulsions, it should again be pointed out t t rapid creaming and necessarily mean rapid coalescence. that attempted tie zeta-potentials to emulsion behavior on storage, but the generality of such an approach has been test is usually carried out , and the Philsoppy here is to intensify the collision frequency between globules.
5. PHYSICAL STABILITY OF POWDERS
Pharmaceutical powders are for reconstitution into either suspensions or solutions. A prescription example of the former is chloramphenicol palmitate, where the arried out by the pharmacist prior to dispensing. An example tamucil, where the customer reconstitutes the product of solutions are AchromycinFM(which is a parenteral the-counter examples of oral solutions of this type are older produ gna Granules (LederleTM). Analogies in the food area are fruit hich are sold in packets and reconstituted by the consu~er to a certain volume. The main physical concerns in this type of product are appearance, organoleptic properties, and ease of reconstitution. nly the latter will be treated here. There are several reasons a powder may change dissolution time as a function of storage time. The most common reasons are (a) cohesion, (b) crystal growth, and (c) moisture sorption, which causes lumpingup of powders. The latter is simply due to the dissolution and bridge-forming that occurs and is akin to what happens in wet granulation.
There are two situations in whichOne is due to the polymorphism. the original product is either a metastable polymorph or amorphous, the conversion may occur in storage. For this to happen, some stress, e.g., the presence of moisture, must occur. The stress need not necessarily be moisture, conversion of a small amount of powder might occur in the filling head of the filling machine and then propagate in time. If the content of the drug substance is such that there are no neighboring drug particles, then this conversion is limited. Particularly, contact points allow for propagation of conversions in situations where the spontaneous nucleation prob- ability is low. The presence of moisture will accelerate conversions of this type, once a seed of the stable polymorph (or in the amorphate situation, once a crystal) has formed. Crystal growth is, per se, not to be expected. It is true that, by the Ostwald-Freundlich equation, a larger crystal is thermodynamically favored over a smaller one; but the energy differences in the usual particle ranges is small and the activation energy high, so that the likelihood is rather low. If sufficient moisture is present so that the vapor pressure in the container exceeds that of saturated solution, then some of the drug will dissolve in asorbed moisture. Fluctuations in temperature are never absent and would cause dissolution followed by precipitation, and this can lead to crystal growth. In cases where a drug substance is capable of forming a hydrate, and where an anhydrate is used, growth by way of hydrate formation is possible. Ease of reconstitution is usually carried out subjectively, in that a tester carries out the reconstitution in the prescribed manner and records the length of time required to finish the operation. For this purpose it is important to have detailed directions on how the reconstitution is to be carried out, and to be sure that there is no operator-to-operator performance bias. To insure the latter, a set of operators is usually selected for the operation at point in the stability history. These operators will then be the test instruments for all testing of reconstitutability of oral powders. The manner of screening operators could be as follows.Arandom sample is taken of a batch of a product. Random sets of four are taken from this random sample, and e.g. three operators tested. They are each given four samples to reconstitute on the first day, four on the second day, and four on the third day. It is a good policy to have two batches and mix them by day and operator, so as to carry out the test in a blind fashion. The results of such a screening.
As mentioned, the most common reason for increases in reconstitution time upon product storage is that the powder becomes more “lumpy” through cohesion developing over time or because it becomes coarser due to crystal growth.
The physical properties associated with tablets are disintegration, dissolution, hardness, appearance, and associated properties (including slurry pH). For special tablet products (e.g., chewable tablets) organoleptic properties become important. These have been described earlier, but in the case of tablets, the chewability and mouth feel also become of importance. The properties will be discussed individually below.
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