ACCELERATED STABILITY studies : ACCELERATED STABILITY studies Presented by :
Nilesh R. Rarokar
S.K.B.College of Pharmacy,New Kamptee
Dist -Nagpur NEED OF ACCELERATED STABILITY STUDY : NEED OF ACCELERATED STABILITY STUDY The stability of pharmaceutical preparation should be evaluated by exposing the product to normal shelf condition for a year or extended period, but
-the rate of decomposition is slow at room temperature.
-such method is time consuming and uneconomical.
Therefore, in practice methods are devised to accelerate the rate of degradation by keeping the products at various temperature, light and humidity conditions. ACCELERATED STABILITY studies : ACCELERATED STABILITY studies Shelf life is officially defined as the time laps during which drug
product retains same property and characteristic that it
possessed at the time of manufacture.
It is generally expressed as expiry period or technically as
shelf life. At first the evaluation of pharmaceutical preparation were
done by observing them for a year or more than that when would
remain in stock and use.
Rate of decomposition of pharmaceutical preparation is slow and
uneconomical process. Hence to study stability of pharmaceutical
preparation accelerated stability techniques are used. Objective: : Objective: To predict shelf life of product by accelerating rate of decomposition preferably by increasing the temperature.
To serve a rapid means of quality control. To serve as a rapid means of selecting the best formulation
from amongst a series of similar formulations of the product. Common high stresses during stability testing : Common high stresses during stability testing Temperature: Increase in temperature increases degradation. Hence, preparation are subject to different elevated temperature .At various time interval, samples are withdrawn, extent and nature of degradation is determined.
Humidity: High humidity condition accelerates decomposition that results from hydrolysis. Product without containers are exposed to high humidity condition, usually in humidity chambers and analyze at regular interval.
Light: Artificial light of varying intensity can be used to accelerate the effect of sunlight. The light source should however emit similar radiation as the sunlight. : Many formulation contains the adjuvant along with drug but the drug degradation in mixture has to be studied individually but it will be more tedious hence gross picture on stability is evaluated.
Degradation properties like change in concentration, color, etc. should be decided.
Physical stability like change in viscosity for suspension, ointment and number of globules for emulsion.
Chemical reaction are always advantageous to predict stability. Salient features: Slide 7: Stability indicating assay method is very essential. Prepare an analytical method for estimation of drug but degraded substance should not interfere.
Degradation product can also be estimated provided that starting material does not interfere.
Some degradation properties should be estimated as a function of time by stability indicating assay. Slide 8: As per kinetic principles the linear relationship with time should be established and order of reaction is determined.
Plot of temperature vs. chemical degradation plotted linear relationship.
Statistical methods are used to predict shelf life with accuracy and to estimate errors.
Conclusion with accelerated stability studies should be correlated with that obtained at normal storage condition.
Pharmacological experiment and preclinical experiment were performed i.e. efficacy, safety and toxicity. Slide 9: 1)Physicochemical properties
-Color/clarity of solution
-Thermo analytical stability *Melting point *Polymorphism
3)Microbial properties -Microbial purity
o Testing scope for drug substances: Slide 10: PREDICTION OF SHELF LIFE Steps involve in prediction of shelf life: 1.The preparation divided into different portions and stored at different elevated temperature.
2.Samples are withdraw at various intervals of time and remaining concentration of active ingredient is measured.
3.The order of reaction is determined by suitable method.
4.Then amount of drug degraded can be determined. Slide 11: Testing scope for Tablets
I. Physicochemical properties-
Appearance, hardness, disintegration,
II. Chemical properties-
Assay, degradation product
III. Microbial properties-
Microbial purity METHOD FOR ACCELERATED STABILITY STUDY: : METHOD FOR ACCELERATED STABILITY STUDY: The sample stored at high temperature are examined for physical and chemical changes at frequent intervals &changes are noted (usually samples stored at 50 c or -200c )
It is excellent stable if no change after 30 days at 600 c.
Samples stored at 50 c & room temperature for as long as 6 months
Data obtained at elevated temperature determined by arrhenius plot which shows the degradation rate at low temprature . Elevated temperature studies(30 0,40 0,50 0,60 0) Elevated temperature data plotted in arrhenius graph where log of degradation constant vs reciprocals of absolute temperature . STUDY UNDER HIGH HUMIDITY : STUDY UNDER HIGH HUMIDITY Presence of moisture may cause hydrolysis and oxidation.
These reactions may accelerated by exposing the drug to different relative humidities.
Control humidity by Lab dessicator (saturated solution of various salts).
Closed dessicator are placed in an oven to provide constant temperature. PHOTOLYTIC STUDY : PHOTOLYTIC STUDY Drug substances fade or darken on exposing to light,can be controlled by using amber glass or opaque container or by incorporating dye to mask the discoloration.
By exposing drug substance to 400 & 900 (FC)of illumination for 4 & 2 weeks to light and another sample examined protected from light . Results found on appearance and chemical loss may be recorded.
Comparing color or using diffused reflectance spectroscopy for examination.
e.g. cycloprofen becomes very yellow after five days under 900 foot candles of light.
. OXIDATION STUDY : OXIDATION STUDY Sensitivity of the drugs to atmospheric oxygen must be evaluated from which it should be packed in inert atmospheric condition with antioxidants is decided .
Here, high oxygen tension plays important role to investigate stability
Usually ,40% of oxygen atmosphere allows for rapid evaluation.
Results were correlated with inert & without inert condition .
Dessicators equipped with 3 way stopcocks are useful for study. Slide 16: Liquid preparation e.g.. Solution are stored at elevated temperature viz. 30,40,50,600 c. In addition sample should be studied at 400C,75% RH and incubator temperature
To conform the results obtained form accelerated stability studies conduct the experiment simultaneously at room temperature i.e. 300C, 70%RH and or refrigerator temperature(4-50C).
During different time intervals samples are withdrawn as given below:
3 months interval during the first yr.
6 month interval during the 2nd yr and yearly their after.
Radio pharmaceuticals which may degrade rapidly for that more frequent sampling is necessary. Slide 17: The method of accelerated stability techniques based on principle of chemical kinetics demonstrated by Garrett and Carper.
According to this techniques the K values for the decomposition of drug in solution at various elevated temperature are obtained by plotting the graph of conc. vs. time as shown below Slide 18: Arrhenious plot are used for predicting drug stability at room temperature where specific rate of decomposition are plotted against reciprocal of absolute temperature as shown graph. Slide 19: Where log % of drug remaining are plotted against time in days and t90(i.e. the time for potency to fall to 90% of the original value) is read from the graph as shown below. Amir Jahed suggested another method for stability technique. Slide 20: In the graph log time to 90% is plotted against 1/T and the time
at 250C give shelf life of the product in days.
From the graph result of decomposition by t90 value is 199 days. Slide 21: Different climatic condition prevalent in different countries.
Mediterranean zone= 250C(60%RH)
Tropical moist =300C(70%RH)
Desert zone=300C(35%RH) Typical Expected Results : Typical Expected Results Slide 23: Limitations:
Accelerated stability testing are valid only when the breakdown depends on temperature.
These are valid only when the energy of activation (Ea) is to be 10 to 30 kcal/mol.
If Ea is less than 10kcal/mol then the rate of decomposition will be faster than the normal storage condition. The elevated temp has very little influence on the decomposition. Slide 24: . These are meaningless when product containing methyl cellulose get coagulated, protein get denatured,emulsion get breaked and suppository get melt under exaggerated temperature. The shelf life for 1 set of preparation not be applied for other of same drug.
When degradation is due to diffusion microbial contamination photochemical reaction and excessive agitation it is of little use If Ea is greater than 30 then very high temperature will require to enhance rate of decomposition . Slide 25: THEORY AND PRACTICE IN INDUSTRIAL PHARMACY,LACHMAN.
PHYSICAL PHARMACY,SIXTH EDITION,ALFERD MARTIN
REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY,
21st EDITION REFFERENCES: THANK YOU! : THANK YOU!