PHYSICAL STABILITY TESTING OF DRUGS AND DRUG PRODUCTS

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CLOUD TIME
Sometimes a cloud will appear in a product as the storage time progresses, and this  is most often due to chemical  changes  in the system.  If for instance an ester (e.g., polysorbate, which is a fatty acid ester) hydrolyzes, then the produced acid may be poorly soluble. If the solubility is denoted S, then the following holds:  If the reaction in general is written


Where A is a drug of initial concentration A0 and is the decomposition product with ility S (which is assumed to be limited.

Arrhenius plotting. Such plotting is quite predictive, The precipitation may also occur by the solubility product being exceeded, or from any situation leading to a product with limited solubility. There are other causes for precipitation on storage, one being the original use of a metastable form, so that the solutions in question, in fact, are super- saturated solutions. It was the author's experience, at his tenure at Hoffmann-la Roche in 1965, that a product to be introduced (Taractan Injectable) was in this category. Several pilot batches had been successfully made, but the first production batches precipitated, a more stable polymorph crystallizing out, This necessitated reformulation to a lower strength (corresponding to the lower solubility of the stable polymorph) and subsequent resubmission of data  to the FDA. This points out the importance of careful preforrnulation studies of the solubility of compounds. Errors of the above type are costly, both in terms of resubmission and in lost market time.  Even  official products fall into this category.

The viscosity  of  these agents is often Ingham bodies,  i.e.,  they posses a yield value. The correct way  of checking the is, therefore, with  e.g. cup and bob viscometer, so that a rheogram can be drawn. In this fashion it is possible to check both changes in yield  value and slope of the rheogram (apparent viscosity). For very liquid solutions (dilute aqueous solutions) this is  difficult, and most often it is  best  followed  by the use  of an  stwald-Fenke  pipette two pipettes (with different flow should flora time should be used in is  case,  because the once in the measured  vise erasure of the yield  value (although calculation of the yield  value from the difference  is a priori not  not yield  value and apparent viscosity are functions of concentration t al.,  1980); in a multicomponent system~ there will  usually  be one moment responsible for viscosity, and it is the breakdown of this one compound that would  be  of importance. often when drastic occur in viscosity, bacterial contamination can be suspected. precipitation is  tied into solubility, as seen in the foregoing.

(b) ORAL SOLUTIONS
The main  types of changes  in appearance of oral solutions (syrups,elixirs,etc) are loss of  dye, precipitation, and bacterial growth. Precipitation has already been dealt  with to some  degree, but some  cases particular to oral  solutions will  be mentioned. Change in  dye content will  be treated below.bacterial growth will  be treated separately.

3. PHYSICAL STABILITY OF DISPERSE SYSTEM
Disperse  systems are suspensions and emulsions. The rationale for the Physical tests carried out on these will  be  discussed  below.

A. SUSPENSION
It would be desirable to have a suspension that did not settle (and there are such suspensions), but the general  rule  is that a suspension  will settle, and therefore there are two parameters that  are followed in this respect,  namely sedimentation rate  and sedimentation volume.  When the sedimentation volumes are small, then there is a tendency for the suspension to cake, and hence various types of shaking tests are carried out. Tests can be purely  subjective, in that a tester notes that e.g. the suspension after three months’ storage at 25°C was  “difficult to resuspend,  leaving  some cake at the bottom,” Such  subjective tests should always be included in a pro but more quantitative means are desirable also. Atypical quantitative test is to rotate the bottle under reproducible conditions. The type of setup used for solubility determinations is a good  type apparatus for this purpose.

One way  of accelerating the settling is to place the suspension product on a shaker at e.g. 37°C. This makes particle movement more rapid and allows the fine particles to slip into the interstices of the larger particles, hence promoting a close packing.  This can then be used to judge qualitatively whether caking will take place. It might be thought that centrifugation would  be a good way in which to ‘‘accelerate’~ sedimentation, and the Stokes  law  indeed  predicts this. However, it gives  only an acceleration of the “initial settling rate,” and the further settling, and the caking phenomena in which the formulator is interested, are not well  predicted by this method. Some  caking  is due to crystal growth, and this is  accelerated by the use  of freeze-thaw tests, i.e., alternating the temperature every 24 h from e.g. 25°C to -5°C  (or some other low temperature above the freezing point of the product). The tem- prelature cycle  will promote crystal growth, and the effect of this on the product can be assessed. The freeze-thaw  cycle has the advantage of emulating (and overstating) some real conditions to which the product could be exposed during shipping. Zapata et al. (1984)  have  described the effect of  freeze-thaw  cycles on aluminium hydroxycarbonate and magnesium hydroxide gels. Coagulation after freeze-thaw  cycles  led to the formation of aggregates that were  visible.  These aggregates were particles in a primary minimum, and these  were  only reseparable by ultrasonic treatment. The freeze-thaw  cycle  affected content uniformity of both the gels, but the treatment did not alter the surface characteristics or the morphology (as judged by x-ray  powder diffraction). It  cause a reduction in the acid neutralization rate, and the rate of sedimentation increased. The effect was pronounced after the first cycle (and indeed most of the effect occurred at this point). The duration of freezing  was not important, but the aggregate size  grew  inversely with the rate of freezing. The use  of polymers in the suspensions  reduced the effects of the freeze-thaw  cycle.

Freeze-thaw cycles  (aside from being a stability monitoring tool) can be  used to screen products as well, the best  of a series of suspensions or emulsions  being the one that stands up best to the test. This on the surface may  be logical, but without a theoretical basis it is  difficult to judge the generality of such a statement.

B. SEDIMENTATION VOLUME
If a suspension  is particulate, then the particles will (approximately) settle by a Stokes  law relation, i.e., the terminal velocity, v, is  given  by


where the constant g is gravitational acceleration, A p is the difference  in  densitybetween  solid and liquid, q is the viscosity of the liquid, and d is the diameter of the particle. The final apparent volume of the sediment, provided it is  monodisperse, would  be  given  by the fact that in cubical  loose  packing a sphere of diameter d will occupy the space of its confining  cube, i.e., the sedimentation volume  will  be


where n is the number of particles per cm3 of suspension.  Since their density  is p g/cm3, then (denoting the dosage  level Q g/cm3) the following  holds:


so that, solving for n,


which inserted in gives


Hence it becomes difficult to separate them, and the precipitate becomes a cake.  This  would prevent redispersion by shaking and would make proper dispensing  impossible. It is a for- mulation goal to prevent this from happening, and this is done by adjusting the zeta potential, as will  be  discussed shortly. From a formulation point of  view, it is better to have the particles at larger distances,  e.g., in the secondary  minimum  occur- ring at longer distances. Adiscussion of the connection between caking tendency and the so-called zeta potential is  beyond the scope  of this book. Suffice it  to state the following: particles are suspended in a liquid, they acquire a charge (and the liquid acquires a similar opposite charge, to maintain electroneutrality). The zeta potential is related to this charge, and caking is prone to happen if the charge potential is outside a range of -10Mvto +10  mV. If the zeta potential is  high it can be lowered by the addition  of negatively charged ions. Highly  valent ions (e.g., citrate) are preferable. On the other hand, if the zeta potential is  low, then it  can be  increased by the addition of positively charged ions (e.g., aluminium ions). The zeta potential is  measured  with a zeta meter, In this the particles are placed in an electrical  field  (between two electrodes, the voltage of which can be adjusted), they are tracked under a microscope, and their velocity  is determined. The relation of  velocity to voltage allows determination of the zeta potential. It is  worthwhile  occasionally to check the zeta potential in a stability check  of suspension (and emulsion) products.

The zeta potential is  close to zero, the suspension  will  be  flocculated,  i.e., the particles are positioned in the secondary minimum. The floccules are large and hence settle more slowly, but on the other hand the sedimentation volume  is large. Since the particles are in the shallow  minimum  (small potential, i.e.,  easy to disrupt), they are easy to resuspend.

There are suspensions that  do  not settle. Here the yield  value of the suspension is so large that the gravitational force  does not exceed it. In this case it is  very important  to carry out complete  rheological  profiles at different time points in the stability program, to insure that the yield  value  is not changing. In such a system the yield value  is a function of the solids content and the viscosity  of the medium.  If the viscosity imparting substance deteriorates, or if the flocculation characteristic (the “diameter” of the particles)  changes, then the yield  value  may change, and what originally  was not prone to cake might at a later time  have  such a propensity. It has been stated elsewhere that for Ingham bodies, a yield diameter of the bottle can be calculated and below this bottle diameter there will  be no settling.

C. TEMPERATURE TESTING OF DISPERSE SYSTEM
A
suspension  is, as the name  implies, a two-component  system  consisting of a solid and a liquid  phase. (Gas phases are considered  nonessential in this connection). Obviously, the solubility of the compound is a function of the temperature, and at a given temperature above 25°C this solubility  will  be reached. Testing about this temperature obviously has no meaning as far  as suspension stability (neither physical nor chemical)  is  concerned. Prior to starting a program, this temperature should be established, so that unnecessary  sampling stations can be avoided.

D. SEMISOLID SUSPENSION SYSTEM (OINTMENT, SUPPOSITORIES)
Some semisolid systems (ointments and suppositories) are suspensions. Their testing is not different, in general philosophy, from what is described above, except that the archeology is  checked  differently.

The factors checked for in stability programs of such products are the following:
1.  Consistency fell to the touch
2. Viscosity
3. Polymorphism

It is mentioned elsewhere that migration of a “disperse” phase within a semisolid product is quite possible when another phase  is present. This situation may  occur in the case of the use  of benzocaine in, for instance, a suppository wrapped in  aluminum  foil coated with  polyethylene.  Polyethylene lining of aluminum wraps of suppositories is  used to prevent contact between the metal and the suppository, and in most cases this has a positive  effect. However, a partitioning of drug or additive between the two phases  may be possible if the drug or additive is  suspended in the suppository. Denoting its solubility in the polyethylene S, and the solubility in the suppository base Ss, the compound would disappear from solution in the suppository at a rate proportional to Sp - Ss, and “disappeared” compound would  be  replenished by dissolution from the solid  phase. The rate of disappearance would be  governed in that the value of Sp would increase by a sigma  minus relation (i.e.,  in the same manner as the appearance of decomposition product in a first-order reaction), and this then would  be the over- all “loss” of compound as a function of time.  Since this is a first-order overall relationship, the “decomposition” would, initially, appear to be first order.

E. OINTMENT AND TRANSDERMAL
Polymorphism can be followed by x-ray analysis and in  some  cases by thermal methods. There is, in fat systems, the possibility of trans etherification, and this can be tested for chemically. The problem of morphology changes is often of particular importance and of particular frequency  in the case of suppositories. In this type of product, it is also important to check for migration of suspended/dissolved substances. Often a sub- stance is added to a suppository as a suspended particle, which is  soluble in the suppository base to some extent. The phenomenon of dissolution will, of course, become  evident by checking the particle size as a function of time.  If a substance is soluble in the base, then it is preferable (if possible) to saturate the base  with it at the onset. For this reason it is necessary to determine the solubility (S gm/gm) of the drug (or other) substance in the base. A Van’t Hoff plot [solubility as a function of temperature (T’K), i.e., plotting ln [q versus 1 /U will allow extrapolation to room temperature. In manufacturing it is  advisable to dissolve the drug (or other substance) to the extent of its solubility during the intermediate temperature phase of manufacturing (where the preparation is  still quite fluid) and then suspend the rest at a lower temperature. An example  is ascorbic acid, which  is a good antioxidant in Carbowax bases. To exert its antioxidant action it must, however, be dissolved (and it is quite soluble  in  polyethylene  glycols). Dissolved drug (or other substance, e.g.,  benzocaine)  will  diffuse  in the suppository base, and can, for instance, partition into polyethylene  linings of the suppository wrap.

Release rates are important in many topical preparations in particular in transdermal preparations. Here there are several investigational methods available.

In-vitro methods involve  placing the ointment on a membrane and Measuring the appearance of drug in a receptor compartment on the sink  side of the membrane. oelgaard and Mollgaard (1983) have, for instance, described the in-vitro release of  linoleum  acid through an in-vitro membrane. They mounted abdominal human skin in one case and skin from hairless rats in another to open  diffusion  cells. The dermal side  was bathed with a rece tor medium stirred at 37°C. The medium  was 75 mL, of 0.05 N phosphate buffer ”-7.4) which contained 0.05% ic  F68 and 0.01% butylhdroxytoliene,  alter two ingredients added in to increase the lipid solubility. Linear, Fiction diffusion  curves  were obtained. In a stability program, such tests are obviously  useful and should be repeated periodically, but an “internal standard” or “calibrator” should be  use  i.e., a stable test substance, the diffusion of which  is  known  (e.g.,  salicylic acid). their pseudo-in-vivo methods involve  shaved or hairless rabbits, or cadaver skin. The interaction between ointment and container (patch) should also be part of the stability program. Some  of the testing applicable to semisolid  emulsion  systems  is also applicable to ointment systems and will  be discussed at a later point.

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