PHYSICAL STABILITY TESTING OF DRUGS AND DRUG PRODUCTS

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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
3. Sedimentation/creaming
4. Caking/coalescence
5.  Consistency
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.

A.    TRANSDERMALS
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.

(a) PARAMETER
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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