PHYSICAL STABILITY TESTING OF DRUGS AND DRUG PRODUCTS
Seth G. L. Bihani S. D. College Of Technical Education,
Institute Of Pharmaceutical Sciences & Drug Research, Gaganpath,
Sri Ganganagar, Rajasthan 335001
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
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.
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.
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.
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.
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).
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