Skip to main content

PHYSICAL STABILITY TESTING OF DRUGS AND DRUG PRODUCTS

 

Clinical courses

About Authors:
L.D.Budania
Seth G. L. Bihani S. D. College Of Technical Education,
Institute Of Pharmaceutical Sciences & Drug Research, Gaganpath,
Sri Ganganagar, Rajasthan 335001
*ldbudania@gmail.com

ABSTRACT:
Stability is an essential quality attribute for drug products. If there is any functionally relevant quality attribute of a drug product that changes with time, this evaluation checked by pharmaceutical scientist and regulators who quantify drug product stability and shelf life. The rate at which drug products degrade varies dramatically. E.g. radiopharmaceutical products. Since the evaluation of the stability of drug is highly specialized and esoteric nature. Drug stability concerns about drug product safety, efficacy, and quality, found it to appropriate. Stability studies are done through the regulatory agencies such as FDA and HPB (health protection branch).


Reference Id: PHARMATUTOR-ART-1527

1. INTRODUCTION
It was at the time of manufacture, and more importantly, it may not meet the minimum required for efficacy. For a solution, a precipitate may have occurred. This may not affect the chemical content, but for a parenteral product it would, obviously, be quite unacceptable and for an oral solution it would also be unsatisfactory, because the dispensing pharmacist would rightfully question the integrity of the product. The caking of a suspension impairs the dispensing of a known amount of drug in a teaspoon, and a separated or broken emulsion or cream obviously will not have the same emollient properties as would a proper product. Physical stability will be treated by product category in the same order as in the case of chemical stability.The formulation is totally unchanged throughout its shelf life and has not suffered any change by way of appearance, organoleptic properties, hardness, brittleness, particle size etc.

Physical degradation may change their pharmacological effects, resulting in alter efficacy therapeutic as well as toxicological consequences. Because pharmaceuticals are maintain their quality until the time of usage or until their expiration date. The most easily understood and most studied form of drug instability is the loss of drug through a chemical reaction resulting  in reduction potency. Loss of potency is a well- recognized cause of poor product quality.

2. PHYSICAL STABILITY OF SOLUTION
Solutions are broadly divided into two categories: oral and parenteral solutions. Appearance, in both cases, is an important factor.  In the case of oral solutions, organoleptic properties are also of great importance. Organoleptic evaluation is usually done subjectively, i.e., a tester (operator, technician), will judge the product and score it, either numerically or descriptively or both. In the case of appearance of solutions, there should always be a subjective statement (quantitative or subjective description) even if more quantitative instruental parameters are recorded. A few words are therefore in order regarding organoleptic and appearance testing.

A. ORGANOLEPTIC TESTING
For organoleptic testing it is important to establish a test  panel early in the stability program. (or if a stability program is in place, but no such testing is carried out, a test panel should be selected at the first opportunity when a product with important taste or odor properties is  placed on stability) Many companies utilize just one tester for the task of organoleptic testing, but this can be shortsighted, because the tester may leave, go on vacation, or become  ill, and in that case the logical solution is to assign  someone  else to the task. There may  be an evaluational bias  between the two testers, and this should be established at the onset. First of all, the depth of organoleptic capacity should be tested. This can be by asking the tester to taste serial dilutions of a bitter substance (e.g.,  quinine). e a sensitivity  level can be established.Acontrol of e.g. water or high dilutions should always  be part of the protocol. It should be noted that the  technicians are not taste testers in the ordinary sense. That is, it is not necessary to match their “likings” to  that of the general public. Rather,  it is important  that they can (a) duplicate their results and (b)  remem- ber them, since  they  will be asked to taste a preparation that they  originally  tested 3  or 6 months earlier. In so doing they  would  have to score the degree of flavoring, e.g.,  is it less than originally present, i.e.,  is the flavor  being lost? They  would also have to be able to describe the flavor  well  originally. For example, if the chemical is  slightly anesthetizing, the duration of the anesthesia would be important. If there is interaction with a plastic bottle, are off  flavors appearing in the product? Finally it is important  to screen  several testers to ascertain that they  give the “same result.” In describing the flavor, several categories can be  used  (degree of sourness, degree of saltiness, level  of flavor, type of flavor). Each of these  may be assigned to a level.Aflavor  profile  may  hence  be established, and this can then be reestablished at several  time points in the room-temperature storage. It is not recommended to evaluate results from higher temperatures (although they  may be carried out).

In aquous  solubility of a drug substance  is a fundamental property  that should be  evaluate early discovery. Lack of solubility can effect  efficacy  and toxicological relevant  exposure in animal.this characteristic  will also  affect the future developability of the formulation efforts for the compound.solubility depend upon salvation energy solvent.in the solvent overcoming both the crystal lattice energy of the solid and the energy of create space in the solvent  for solute. Thus the solubility of compound depend not only properties of the drug molecule itself  such as polarity, lipophilicity , ionization potential and size but  also on properties of the solvent  and  solid throughout discovery range from the method that dilute dimthylesulfoxide  stock solution in aquous buffer  and mimic the method in which high throughout  assay are run, to those measuring psedoequilibrium solubility using crystalline solid and aquous buffers. Detection methods include turbidimetric method , uv plate readers, liquid chromatography (LC)/uv  and LC/MASS spectroscopy. The solubility method chosen depend upon the desired time, quantity of compound and the quantity of compound  and quantity of results requires.

The factor affect as-
(a)  Dielectric constant
:
The rates of degradation between ions and dipoles in solution depend on the bulk properties of the solvent, such as the dielectric to a variation in rate constant with change in dielectric constant. For example ion depolarization rate constant have been related to dielectric constant D of the solvent through in k?


Where the kd  that is rate ?∞ is the rate  constant  at infinite dielectric constant ,  ZA, u and r are ion charge , dipole moment  and the shortest ion dipole distance, respectively and k is the boltazmann constant. The term  ?represent the alignment of reactant and cos?is unity in the case on aligment.  Thus  as the dielectric  constant  increase , the rates of anions , dipole reaction decrease and the rates of cation dipole reaction increases.  As indicated by linear relationship  with positive slop in log k  verses 1/D  plots, the hydrolysis rate constant for chloramphenicol in water propyl glycol mixture  increase with deceasing dielectric constant, suggesting a hydronium ion dipole reaction, whereas in alkali its anionic form is degraded  by hydroxide ions. The dipole- cation reaction at   PH 1 exhibit log versus 1/D  Plots  with a negative  slope,  suggesting that reactant alignment is opposite to the head  on alignment. The observation that the rate of anion , anion reaction at pH11 is independent of dielectric constant has been explained by assuming  that a change in the bulk dielectric constant is not reflected in the microscopic  dielectric  constant and no effect on the reaction.Effect of change in solvent diectric constant  on the degradation rate of chloramphenicol.

(b) VISCOSITY
Viscosity of solution serve the palatability or improve portability. This can be achieved  by increasing the sugar content in the syrup or adding viscosity controlling agents , such as polyvinylpyrolidone and various cellulose derivative like methyl cellulose or carboxy methyl cellulose.

(c) Taste ( flavour )
Mostly combination of flavouring agent are used in industries. Apart from this, methanol and chloroform also used as desensitizing  agent because they provide the odour to preparation along with some local anesthetic effect. In food industries the monosodium glutamate mainly used. The change flavoring agent can be determined  by vapour phase chromatography.

(d) Colour
Colour is measured by spectrophotometrically. Clarity measured by passing the beam of light on sample solution and measured  scattering. Turbidity is measured by turbidometry.

(e) Integrity of container
Some plastic container may shrink when contact with the preparation or may cause corrosion of cap. Sometime the glass container may change the pH of solution and may affect the stability of preparation. By investing the intrinsic stability of the drug it is possible to advise on formulation approaches and indicate type of excipient, specific protective additives and packaging which are likely to improve the integrity of the drug and product. As various pharmaceutical dosage form present unique stability problem, they are discussed under.

B. SUBJECTIVE APPEARANCE TESTING
Solutions, particularly parenteral solutions, may have a tendency to discolor slightly. 0ften it is not possible, within analytical sensitivity, to establish either the source of e color or the level of the substance causing it, In this case it is a good practice to use a color standard to describe the “intensity” of the discoloration. For instance, uses the so-called Roche Color ~standard (RCS),  which  uses pound (the identity of  which  is a secret) that can be reliably reproduced and has exceptional color stability. Making up serial dilutions of this solutions of different “slight” discolorations; they are denoted so that a solution can always be compared in this fashion, old-fashioned Dubuque colorimeter (which can be used with advantage in this type of situation).

Where q is a constant, t is time, and XW is found by iteration. This allows (from accelerated studies) a visual estimate of the worst appearance that a product could take on.

(a) PARENTERAL SOLUTION
In Parenteral solutions, physical stability includes interaction with a container and changes in chemical composition that give  rise to physical  changes. For instance, may discolor slightly without showing detectable changes in content of parent compound. Such discolorations can be followed as described immediately above, and at times they are detectable analytically. They are often oxidative in nature and metal ion catalyzed. Such a case in captopril .It has reviewed the stability aspects of parenteral products coloration is often either photochemical or oxidative. Has summarized the usually used antioxidants and chelating agents.

SWIRLY PRECIPITATION
Often a parenteral solution will develop a swirly precipitate upon storage. This is Most prevent in vials and is usually an interaction with either the glass or stopper.it   may  be  difficult for the uninitiated to detect such  slight  changes, and reason to use for this type of evaluation is a parenteral inspector. It is difficult to estimate the extent of the precipitate; it can be done by mechanical counting (e.g., with a Coulter counter), but the results are difficult to interpret, Often the count pond to the “severity of the swirl.”  re to the point is  how  many a box of e.g. 144 vials  is  placed o S type of stability, then the vials can be examined from time to time, and one may establish how  many  vials have  become  swirly. This number  be treated in proper fashion to evaluate the severity of the problemasmentioned, the occurrence of swirls  is  usually a container interaction, and a change in the stopper or the glass  may often eliminate the problem. Vials should always be stored (a) upright, (b) on the side, and (c)  upside  down to check the inter- action with the stopper. In this way primary evidence can be established as to the culpability of the closure.

WHISKERS
It occurred at the tip of the ampoule in a large percentage of ampoules upon room-temperature storage. This is a defect that will occasionally occur in a product. It is due to pinholes in the glass. The solution wicks out, and the liquid evaporates on the outside. The solid that is formed serves to wick out more solution, and long crystals or “whiskers” may occur.  One might ask why the pinholes have not been detected in the dye test used for autoclaved ampoules. There are two reasons. One is that the hole may  be too small for detection (about 0.5pm is the detection. limit). The other is that the ampoule was tight at the time of manufacture, but the heat sealing  line  was run too rapidly, or the flame temperature was incorrect, so that the glass  did not have  time to anneal pro- pearly, and the strain caused the crack during storage (not immediately after manufacture).

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

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.

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

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.

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

Tablet Hardness
The “hardness” properties of a tablet are usually  assessed by subjecting the tablets to a diametral failure test. The tablet is  placed  between  two  anvils,  one  of which  is stationary. The other anvil  is  moved at constant speed against the tablet, and the force (as a function of time)  is recorded. The force, at which the tablet breaks is denoted the “hardness” and is usually  measured  in kp (kilopond= kilogram force). Other older units (Strong Cobb Units, SCU, or pound force) are used,  usually when  older instrumentation is  used. Until recently,  one limitation was that forces over 20 kp would  simply  register as F > 20 kp. Newer instrumentation allows for quantitation of higher  forces. From a stability point of  view this is important, since the better a parameter can be quantitated, the clearer the picture that emerges  will be.

For good formulations, this  maximum  does not occur until very  high  pressures (outside the range of pressures  used in pharmaceutical tableting). The maximum  occurs because  above the critical pressure, P*, the tablet will laminate or cap, and a laminated tablet  will contain strata of air and hence  be thicker and weaker. Tablet thicknesses will respond in a manner opposite to the hardness, i.e.,  show a minimum  (e.g., at 500 MPa . The reason for this phenomenon  is the following: As applied  pressure  increases, the number of bonds, N, increases as well. ut assuming that there is a number of bonds, N*, that can be formed, then the strength, H.

Its side from the quoted instance of porosity changes and expansion, there are cases  where crystallization of a soluble compound has occurred via the sorbed amounts of moisture in the tablet, This happens most often with  very  soluble  compounds, and in such  cases it is important  to ascertain storage in a dry environment.

A test that is  now a requirement in the ICH Guidelines  is storage in the final container at 40°C, 75% RH. During this test moisture is  usually adsorbed by the tablets, and this can then cause softening of the binder  bridge  because of moisture uptake. At times,  redrying  will reinstitute the original hardness, Sometimes hardening occurs when the asorbed moisture causes recrystallization of a compound or Sexcipient.

Disintegration
Tablets (whether coated or not) are usually  subjected to a disintegration test. The disintegration was the first in-vitro test used by the U.S.P. It is  now not obligatory compendially (but is  recommended); in an obligatory sense it has been  replaced by the dissolution test. This latter, hence,  is the more important test, but it will be  seen that there often is a correlation between the two, and since the disintegration test is  much more easily carried out, a stability program will  check disintegration frequently, and dissolution less frequently, primarily due to labor intensity. The apparatus used (U.S.P. XX, p.  958)  is  shown  schematically in Fig. 22. It is an apparatus where  six tubes are placed in holders on a circular screen,  which  is then raised and lowered  between 29 and 32 times  per minute through a distance of 5.3-5.7  cm in a 1000 mL beaker containing the disintegration medium (either