# Stability Studies by NAITIK THAKKAR

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By: porabhai (120 month(s) ago)

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By: nkbhatta (124 month(s) ago)

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## Presentation Transcript

### STABILITY STUDIES :

GUIDED BY: HARESH MULANI SIR PRESENTED BY: NAITIK THAKKAR (M.PHARM, DEPARTMENT OF PHARMACEUTICS) DHARMAJ DEGREE PHARMACY COLLEGE 1 STABILITY STUDIES

### Slide 2:

STABILITY STUDIES

### FOCUS OF THE PRESENTATION :

3 FOCUS OF THE PRESENTATION

### Slide 4:

4 ENVIRONMENTAL FACTORS ENVIRONMENTAL FACTORS

### ENVIRONMENTAL FACTORS :

TEMPERATURE 5 ENVIRONMENTAL FACTORS Catalyst 10°C rise produces 2-3 fold increase in rate ARRHENIUS in 1889 proposed the following equation which relates the rate constant K to the Temperature K = A e-Ea/RT Where k = rate constant A = frequency factor/ Arrhenius factor Ea = activation energy in Joules per mole. R = gas constant 8.3143 J/K mol. T = absolute temperature in Kelvin

### Slide 6:

6 COLLISION THEORY Reaction rate ∞ No. of collisions per unit time As TEMP. es ↔ No. of collisions es ↔ Reaction rate es Due to this certain drugs Stored at LOW temperature. eg. Biological Products * insulin * oxytocin * vasopressin injection

### Slide 7:

7 EXCEPTION LOW temperature storage may rate of decomposition eg. Rate of polymerization of Formaldehyde below 15°C i.e. On standing, below 15 °C, the Formaldehyde forms Para formaldehyde, which is thrown out of solution as WHITE ppts. TO PREVENT… 10 to 15 % methyl alcohol is added as stabilizer.

### LIMITATIONS OF ARRHENIUS RELATIONSHIP FOR STABILITY STUDIES :

At higher temp., there is less Relative Humidity & O2 solubility, thus hindering the predictability stability of drug sensitive to presence of Moisture and Oxygen. For dispersed systems, Viscosity is decreased as temp. is increased and Physical characteristics may be altered, resulting in potentially large errors in prediction of stability. Different degradation mechanisms may predominate at different temperatures, thus making stability prediction erroneous. 8 LIMITATIONS OF ARRHENIUS RELATIONSHIP FOR STABILITY STUDIES

### WAYS FOR STABILIZATION :

Pharmaceutical product should be stored within the temperature range in which they are stable. They should not be exposed to extremes of temperature. Usually they should be stored at low temperature if they lack sufficient stability at room temperature. There are few drugs on which freezing has an adverse effect, so freezing should be avoided unless until it is stable at such temperatures. 9 WAYS FOR STABILIZATION

### ENVIRONMENTAL FACTORS :

10 ENVIRONMENTAL FACTORS LIGHT Light induce degradation of drug. Drug may be of two types, 1) Photo sensitive (Photochemical reaction) 2) Photo sensitizer (Photosensitization) WAYS FOR STABILIZATION: Suitable packing Photo stabilizer (Light absorber) Protection of drug from light during mfg. Coating.

### Eg. Photo stabilization of Molsidomine Tablet. :

sun light Molsidomine Morpholine dvt. (potential carcinogenic) It was stabilized by.. 1) Incorporation of light absorbing excipients. a) colorants – curcumine(E 100) and azorubine (E 122) b) UV absorber – UV absorber A & B 2) Incorporation of pigments. eg. TiO2 and ZnO 3) By coating a) white coating ( 4.8% TiO2) b) colored coating ( yellow & red iron oxide added to std. coating containing 4.8%TiO2) 11 Eg. Photo stabilization of Molsidomine Tablet.

### CONCLUSION :- :

Pigments are superior to colorants or UV absorber as Photo stabilizing agent. 0.5 % TiO2 – reducing degradation from 33% to 22%. Preblending for 5 min molsidomine with the micronized TiO2 pigment reduces the decomposition of drug. Combination of two Photo stabilizing agents will give complete Photo stabilizing activity. eg. Molsidomine tab. Packed into UV absorbing blisters and incorporation of yellow oxide pigments. 12 CONCLUSION :-

### Slide 13:

13 ENVIRONMENTAL FACTORS pH Acidic and Alkaline pH influence the rate of decomposition of most drugs. Many drugs are stable between pH 4 and 8. Weekly acidic and basic drugs show good solubility when they are ionized and they also decompose faster when ionized. So if… the pH of a drug solution has to be adjusted to improve solubility and the resultant pH leads to instability then a way out of this tricky problem is to introduce a water-miscible solvent into the product. It will increase stability by (a) suppressing ionization, (b) reducing the extreme pH required to achieve solubility, (c) enhancing solubility and (d) reducing the water activity by reducing polarity of solvent.

### Slide 14:

14 For example, 20% propylene glycol is placed in chlordiazepoxide injection for this purpose. Reactions catalyzed by pH are monitored by measuring degradation rates against pH, keeping temperature, ionic strength and solvent concentration constant. Some buffers such as acetate, citrate, lactate, phosphate and ascorbate buffers are utilized to prevent drastic change in pH. Sometimes pH can have a very serious effect on decomposition. So when we are formulating a drug into a solution we should carefully prepare a pH – decomposition profile and then formulate the solution at a pH which is acceptable physiologically and stability-wise also.

### Slide 15:

15 ICH TRIPARTITE GUIDELINES ICH TRIPARTITE GUIDELINES

### Slide 16:

16 Prior to 1960s there were not many controls over introduction of new drugs and also over the assurance of the quality. Around 1970s the pharmaceutical industry started getting Global but the registration of medicines remained a national responsibility. So the companies had to duplicate many time expensive test procedures, in order to market new products, Internationally. All this resulted in unnecessary expenses and long delays in introducing new drugs. So a necessity to harmonize, the testing procedures and regulatory requirements of different countries was felt and the result is the birth of ICH in APRIL 1990.

### Slide 17:

17 ICH The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. AIM: It is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration. OBJECTIVES More economical use of human, animal & material resources. Elimination of unnecessary delay in the global development & availability of new medicines. Maintaining Quality, Safety & Efficacy, and regulatory obligations to protect the public health.

### Slide 18:

18 Q1-D BRACKETING AND MATRIXING Q1-D BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

Outlines recommendations, principles, and considerations for reduced designs. Terms: Full Study Design: samples for every combination of all design factors are tested at all time points Reduced Study Design: not all samples for every factor combination are tested at all time points 19 BRACKETING AND MATRIXING STUDY DESIGN FULL STUDY DESIGN REDUCED STUDY DESIGN MATRIXING BRACKETING

### BRACKETING AND MATRIXING :

Terms (cont’d): Bracketing: testing samples on the extremes of certain design factors (e.g., strengths, container sizes and/or fills) Matrixing: testing a selected subset of the total number of possible samples for all factor combinations at a specified time point, while testing another subset of samples at a subsequent time point 20 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

Basic Principles: some reduced designs may need minimal justification, some designs may require more justification assumptions should be assessed and justified potential risks should be taken into consideration Note: if a reduced design is proposed to be implemented after approval of the original submission, a prior approval application should be filed (e.g., in Canada: a “Level 2 - Notifiable Change”) 21 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

Bracketing - Strengths: Applicable: strengths of identical or closely related formulations Applicable with additional justification (e.g., supporting data): strengths where the relative amounts of the drug substance and excipients vary within the product line Not applicable: different excipients among strengths 22 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

Bracketing – Container Size, Fill: Applicable: same container closure system where either the container size or fill varies while the other remains constant Applicable with additional justification (e.g., supporting data): same container closure system but both the container size and fill vary Not applicable: different container closure systems 23 BRACKETING AND MATRIXING

### Slide 24:

24 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

25 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

Bracketing - Considerations: If stability of extremes are shown to be different, the intermediates should be considered no more stable than the least stable extreme Selected extreme may be dropped from proposed market presentations 26 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

Matrixing: applicable: strengths with identical or closely related formulations container sizes or fills of the same C/C system different batches made with the same equipment and process applicable with additional justification: where the relative amounts of excipients change or different excipients are used not applicable: different storage conditions different test attributes 27 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

Matrixing - Considerations: - Design should be balanced as far as possible so that each combination is tested to the same extent over the intended duration of the study and through the last time point prior to submission - Where time points are matrixed, all selected factor combinations should be tested at the initial and final time points (and the last time point prior to submission) 28 BRACKETING AND MATRIXING

### BRACKETING AND MATRIXING :

BRACKETING AND MATRIXING MATRIXING - Simple design on time points : A true, but not practical, “one-half reduction”

### BRACKETING AND MATRIXING :

BRACKETING AND MATRIXING MATRIXING - Simple design on time points:

### Slide 31:

31 GLOBAL CLIMATE ZONES GLOBAL CLIMATE ZONES

### GLOBAL CLIMATE ZONES :

A very important point in conducting stability studies are the storage conditions. They should simulate the conditions under which the drug substance or drug product is subjected: from manufacturing to final application. Storage conditions are derived from real climatic conditions. 32 GLOBAL CLIMATE ZONES

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34

### Slide 35:

35 Q1-b PHOTOSTABILITY TESTING Q1-B PHOTOSTABILITY TESTING

### Why?Photo Stability Testing…… :

Light can affect drugs, causing chemical changes so… To Evaluate that light exposure does not result in unacceptable change. Provides means of screening drug early in the development process & allows identification of particular photo labile drug. gives idea about how to store drug For generation of photo stability information for submission in Registration Applications for new molecular entities and associated drug products. 36 Why?Photo Stability Testing……

### Systematic approach to Photo Stability Testing :

37 Systematic approach to Photo Stability Testing I) Tests on the drug substance; II) Tests on the exposed drug product outside of the immediate pack; and if necessary ; III) Tests on the drug product in the immediate pack; and if necessary ; IV) Tests on the drug product in the marketing pack.

### Slide 38:

LIGHT SOURCES Combination of visible and UV light PROCEDURE Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter Protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change [ LUX = Is the unit which indicates the intensity or the brightness of the light] 38

### Slide 39:

39 START DIRECTLY EXPOSED YES FORMULATION CHANGE? NO IMMEDIATE PACK CHANGE? NO MARKETING PACK CHANGE? YES MARKETING PACK NO ACCEPTABLE CHANGE? IMMEDIATE PACK YES ACCEPTABLE CHANGE? NO ACCEPTABLE CHANGE? NO REDESIGN PACKAGE OR REFORMULATION TEST END YES YES TEST END TEST END YES DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS

### Slide 40:

40 Summary Stability studies play a central role in drug development. Permits understanding of the molecule Essential for developing analytical methods, selecting packaging and storage conditions for drug substance and drug product Stability data is submitted to Health Authorities to support registration.

### Slide 41:

Lachman L,etal , The Theory & Practice of Industrial Pharmacy,3rd edition, Philadelphia; Lea & Febiger,1986, 764-766 Physical pharmacy by Martin A., James S.,5th Edition , Varghese publishing house,397-432 Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes (Marcel Dekker, Inc., New York, 2000),579-599 Remington “the Science & Practice of Pharmacy “,20th edition,vol 1, Lippincott WILLIAMS & Wilkins,986-989 41 References

### Slide 42:

www.pharmatech / stability testing .com www. Pharmapedia.org ICH HARMONISED TRIPARTITIE GUIDELINES www.ich.org http://archive.amol.org.au/recollections/3/1/08.htm 42 References

### Slide 43:

43 THANKS FOR UR PATIENCE