Stability Studies by NAITIK THAKKAR

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By: jadhavkr (116 month(s) ago)

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By: naitik33 (116 month(s) ago)

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By: porabhai (121 month(s) ago)

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By: naitik33 (121 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 DDPC

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 In 1889 ARRHENIUS 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

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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

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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 predictable 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. 9 WAYS FOR STABILIZATION

ENVIRONMENTAL FACTORS : 

10 ENVIRONMENTAL FACTORS LIGHT Light energy, like heat, may provide the activation necessary for a reaction to occur. Light induce degradation of drug. Photolysis (i.e. decomposition of product resulting from the absorption of radiant energy) has now become an important degradative pathway because of the complex chemical structure of many new drugs.

ENVIRONMENTAL FACTORS : 

Photolysis may be of two types, 1) Photo chemical * 2) Photo sensitization* WAYS FOR STABILIZATION: Suitable packing Photo stabilizer (Light absorber) Protection of drug from light during mfg. Coating. 11 ENVIRONMENTAL FACTORS

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 T & 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) 12 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. 13 CONCLUSION :-

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14 ENVIRONMENTAL FACTORS pH pH influence the rate of decomposition. 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

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15 For example, 20% propylene glycol is placed in chlordiazepoxide injection for this purpose. 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.

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16 ICH TRIPARTITE GUIDELINES ICH TRIPARTITE GUIDELINES

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17 Prior to 1960s not many controls over introduction of New drugs Around 1970s Globalization of pharmaceutical industry but… the registration 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 and the result is the birth of ICH in APRIL 1990.

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18 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 of new medicines. Maintaining Quality, Safety & Efficacy, and regulatory obligations to protect the public health.

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19 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 20 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) at all time points 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 21 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 22 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 23 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 24 BRACKETING AND MATRIXING

Slide 25: 

25 BRACKETING AND MATRIXING

BRACKETING AND MATRIXING : 

26 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 27 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 28 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) 29 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 32: 

32 GLOBAL CLIMATE ZONES GLOBAL CLIMATE ZONES

GLOBAL CLIMATE ZONES : 

A very important point in conducting stability studies are the storage conditions. They should mimic 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. 33 GLOBAL CLIMATE ZONES

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34

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35

Slide 36: 

36 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 leads to unacceptable changes or not ??? 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. 37 Why?Photo Stability Testing……

Systematic approach to Photo Stability Testing : 

38 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 39: 

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] 39

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40 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 41: 

41 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 42: 

Lachman L,etal , The Theory & Practice of Industrial Pharmacy,3rd edition, Philadelphia; Lea & Febiger,1986,764-6 Dr. Ali Javed,Khar R.K,Ahuja Alka,Text book of dosage form design,Birla publication,2004,page110-3. Physical pharmacy by Martin A., James S.,5th Edition , Varghese publishing house,397-32 Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes (Marcel Dekker, Inc., New York, 2000),579-99 Remington “the Science & Practice of Pharmacy “,20th edition,vol 1, Lippincott WILLIAMS & Wilkins,986-9 42 References

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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 43 References

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44 THANKS FOR UR PATIENCE

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