VARIOUS FACTOR AFFECTING STABILITY OF FORMULATION-2

VARIOUS FACTORS AFFECTING STABILITY OF FORMULATION: 

VARIOUS FACTORS AFFECTING STABILITY OF FORMULATION Prepared by SANDIP PRAJAPATI Guided by MR.AKSHAY KOLI

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What does stability mean for drugs and pharmaceuticals ? The stability of the product is its ability to resist deterioration. It is always expressed in terms of shelf life. Stability : is the capacity of a drug product to remain within specifications established to ensure its identity, strength quality and purity. (USP-NF)

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As per USP there are five types of stability studies : » Chemical » Physical » Microbiological » Processing factors » Toxicological

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1 ) Chemical factors: Various ways of chemical degradation includes: hydrolysis dehydration isomerization & racemization decarboxylation & elimination oxidation photo degradation drug – excipients & drug – drug interactions

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HYDROLYSIS Ex- 1)Procaine OH PABA + Diethyl Amine ethanol 2) Chloramphenicol H+ CH3COOH 2-amino1-p-nitro Phenyl-1,3-propandiol + Dichloro aceticacid It is major cause of deterioration of drugs, especially for those in aqueous solution.

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REMEDIES: 1) Removal of water,storage in dry form. 2) Using an insoluble derivative in suspension form. 3) Replacement of water by substantial quantity of some other solvent such as alcohol or polyhydroxy solvent mixtures. 4) By Micellar formation using anionic & cationic surfectants .

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DEHYDRATION Sugars such as glucose and lactose are known to undergo dehydration to form 5-(hydroxymethyl)furural. Erythromycin is susceptible to acidcatalyzed dehydration Batanopride undergoes an intramolecular ring-closure reaction in the acidic pH range due to dehydration There are two types of dehydration process: 1) Covalent dehydration 2) Physical dehydration

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ISOMERIZATION & RACEMIZATION I somerization Conversion of active drug into less active or inactive drug. EX-Vit-A susceptible to isomerization in presence of light. Racemization Conversion of optically active drug into its enantiomer. The best known racemerization reaction of drugs are epinapherine,pilocarpine,ergotamine & tetracycline .

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DECARBOXYLATION Drug substances having a carboxylic acid group are sometimes susceptible to decarboxylation. 4-Aminosalicylic acid is a good example. Foscarnet also undergoes decarboxylation under strongly acidic conditions,whereas etodolac is susceptible to decarboxylation by acid catalysis. This action is minimised by passing CO2 into the solution for one minute & sealing the container so as to make it gas-tight prior to autoclaving. REMEDIES

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Ionic Strength (Primary Salt Effects ) For drug degradation involving reactions with or between ionic species, the rate is affected by the presence of other ionic species such as salts like sodium chloride. Ionic strength affects the observed degradation rate constant, k, by its effect on the activityn coefficients, ƒ. Ionic strength, µ, is described by where Ci is the concentration of ionic species i and Zi is its electric charge.

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OXIDATION Drugs can be affected by the availability of oxygen. Some photo degradation reactions involve photo oxidative mechanisms that are dependent on conc. of oxygen. Oxygen participates as reactant and also alters the degradation rate. Oxygen exists in various states such ground state triplate oxygen, etc.

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The following excipients may have low level residues from manufacture that can lead to oxidative degradation in susceptible compounds.

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REMEDIES: 1) Minimum oxygen level used which may be achieved by boiling the water & allowing to cool in an atmosphere free from oxygen. 2) Hydrogenation of product. 3) Incorporation of inert gas in containers. 4) Use of anti-oxidant. 5)Buffering the solution at favourable pH, Use of metal free solvents.

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PHOTOLYSIS Reactions such as oxidation-reduction, ring alteration and polymerisation can be catalysed or accelerated by exposure to sun or artificial light. Photolytic degradation can be very complex, the products of such degradation being numerous and difficult to identify . Exposure to light can cause discolouration of both drugs and excipients even when degradation is modest and not even detectable analytically . This can lead to “off colour” product, perceived by the patient as a quality deficiency.

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CATALYSIS In parentrals, great care is taken to exclude metals, because only slight decomposition caused by trace metals may cause sufficient discoloration to the product unsatisfactory. Ex of metal catalysed oxidation in pharmaceutical system are cynocobalamine & erythromycin.

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2) Physical factors TEMPERATURE pH AND pH RATE PROFILES BUFFER LIGHT CRYSTALLINE STATE & POLYMORPHISM IN SOLID DRUGS MOISTURE AND HUMIDITY EXCIPIENTS MISCELLANEOUS FACTORS

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TEMPERATURE It is one of the primary factors affecting drug stability. The rate constant/temperature relationship has traditionally been described by the Arhenius equation, k = A exp(-Ea/RT) where E a = activation energy A = frequency factor .

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REMEDIES :- 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.

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pH AND pH RATE PROFILES Second most important parameter. The effect of pH on degradation rate can be explained by the catalytic effects that hydronium or hydroxide ions can have on various chemical reactions. If critical path in a reaction involves a proton transfer or abstraction step, other acids and bases present in solution can affect the rate of reaction.

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A reaction in which hydronium ion, hydroxide ion, and water catalysis are observed can be described by K obs = k H+ a H+ + K H2O + K oH- a OH- Where K obs = sum of specific rate constants a H+ = activities of hydronium ion a OH- =activities of hydroxide ion

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BUFFER These buffer species, like H+ and OH-, participates in formation of break down of activated complexes of various reaction and determine their reaction rate. These catalytic species are referred to as general acid-base catalysts. Studies with phosphate buffer indicates that it enhance the degradation of various drug substances such as carbenicillin etc.

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LIGHT The number and wavelength of incident photons affect the photo degradation rate of drugs. It is not easy to study the effect of light quantitatively as the wavelength dependence of degradation varies among drug substances and because light sources have different spectral distributions. Photo degradation for drug strongly dependence on the spectral properties of the drug substances and the spectral distribution of the light source.

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CRYSTALLINE STATE & POLYMORPHISM IN SOLID DRUGS The stability of drugs in their amorphous form is generally lower than that of drugs In their crystalline form due to higher free energy level of amorphous form decreased chemical stability of solid drugs brought about by mechanical stresses such as grinding is said to be due to change in crystalline state. ex: grinding of aspirin increased degradation rate in suspension form.

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MOISTURE AND HUMIDITY Drug degradation in heterogeneous system such as solid and semisolid states is affected by moisture. Moisture plays important role in catalyzing chemical degradation: Water participates in the drug degradation process itself as a reactant, leading to hydrolysis; hydration etc. Here degradation rate is directly affected by the concentration of water, hydronium ion, hydroxide ion. 2) Water absorbs onto the drug surface and forms a moisture-sorbed layer in which the drug is dissolved and degraded. Ex-Sodium ampicillin , potassium propicillin

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REMEDIES : Maintenance of controlled humidity condition Moisture proof packaging . EFFECT OF SOLUBILITY:- Applicable to drugs in solution form. Ex:- Penicillins are very unstable in aqueous solution because of hydrolysis of β-lactam ring. REMEDIES: Stabilised by using insoluble salts of API. Formulate the drug in suspension dosage form.

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EXCIPIENTS The role that excipients play in drug stability has been extensively reported-e.g.: accelerating the effect of talc on hydrolysis of thiamine hydrochloride, the accelerating effect of magnesium stearate on tablet containing amines and lactose etc. Additional informations include reports on compatibility and incompatibility of drugs. Excipients can affect drug stability via various mechanisms.

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VAPORIZATION Some drugs & pharmaceutical adjuvants possess sufficiently high vapor pressures at R.T. that their volatization constitutes a major route of drug loss. Flavors may be lost from the formulation in this manner. Ex-Nitroglycerine= 0.00026mm at 20˚c = 0.31mm at 93˚c

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AGING: This is a process through which changes in the disintegration &/or dissolution characteristics of the dosage form are caused by alteration in the physico chemical properties of the inert ingredient or the active drug in the dosage form. Ex-melting point of aminophylline suppository increased from about 20 mins to over an hour after 24 weeks of storage at 22 c

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RADIATION Radiation generally used during gaseous sterilization of thermolabile drugs. The exposure also produce deterious changes in the product since the procedures also cause ionization in the irradiated material. Irradiation of a drug in aq. solution produces greater changes than the irradiation of the pure material because irradiation of water produces H2O2,free oxidative action in drug.

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Drugs affected by radiation are: Alkaloids Atropine Steroids Sulphonamides Biological products- Insulin,Heparin.ss All the above ex. are irradiated at low level of 2.5 µ rad.

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EFFECT OF PACKAGING COMPONENTS:- Most commonly employed are CONTAINERS: Glass, Plastic, Metal CLOSURES:- Rubber CONTAINERS : 1) GLASS PROBLEMS : a) Release of alkali b) Release of Insoluble flake ( Alfonso R. Gennaro , Remington: The science & Practice of Pharmacy,Vol-1,Ch-41, Page No-780.)

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REMEDY FOR PREVENTION OF RELEASE OF ALKALI :- By decreasing soda content Siliconization of surface. By replacing sodium oxide with other oxides. Surface treatment by sulphur-di-oxide in presence of water-vapour & heat. REMEDY FOR PREVENTION OF RELEASE OF INSOLUBLE FLAKE :- Flake formation can be prevented by using borosilicate glass Pretreatment of the container with dilute acid .

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2) PLASTIC HIGH MOLECULAR WEIGHT POLYMERS LIKE POLYETHYLENE, POLYPROPYLENE, POLYSTYRENE, PVC ETC PROBLEMS : Permeation of moisture Leaching Adsorption or Absorption Chemical/Physical reaction of contents of containers with product . REMEDY : Lining of the container with an epoxy resin eliminates this problem but has to be evaluated separately for each product. (epoxy lining does not prevent sorption of phenyl mercuric nitrate).

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3) METALS Metals commonly used are tin , plastic coated tin , tin-coated lead , aluminum and coated aluminum . PROBLEMS : a) Reactivity 1. TIN + CHLORIDE ERROSION 2. ALUMINUM + FATTY ALCHOL WHITE REMEDY : Application of an epoxy lining to internal surfaces of aluminum tubes was found to make them more resistant to attack

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REMEDIES : Epoxy lining applied to rubber stoppers reduction results in amount of extractive leached from stopper but no effect on sorption of preservative from solution. However use of Teflon – Coated rubber stoppers essentially prevents sorption and leaching of the rubber stopper. CLOSURES :- RUBBER PROBLEMS : a) Sorption of API into rubber. b) Extraction of one or more components of rubber into vial solution .

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3) PROCESSING FACTORS :- BLENDING FREEZE-DRYING PROCESS POLYMERIC FILM COATING PROCESS MILLING EFFECT OF LOCAL MOBILITY WET GRANULATION FREEZE-DRYING PROCESS POLYMERIC FILM COATING PROCESS EFFECT OF COMPRESSION EFFECT OF LOCAL MOBILITY WET GRANULATION

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BLENDING :- It is most important step for manufacturing of solution dosage form. High speed of mixing may introduce air into the product and slow mixing may not form a satisfactory product. For mixing step, both mixing time and speed should be evaluated for API and Excipients. During mixing some other factors like type of agitator, temperature or vaccum etc. can affect the stability. REMEDIES :- Use of optimum time and rate of mixing. Use of optimum and controlled temperature. Application of vacuum. Use of closed system .

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FREEZE-DRYING PROCESS :- Freeze-drying process also affects the stability of product & there are various substances used for the process of freeze-drying which also leads to either increase or decrease in the stability. EX:- Freeze drying was found to have destructive effect on the ordered structure of starch & this effect varied with respect to preparation condition.

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MILLING The milling process results in a reduction in the particle size of a given material and can be conducted using the mildest conditions possible to render a sample homogeneous, or can use more rigorous milling to reduce the primary particle size. These physical changes in the state of the drug substance can alter the stability, dissolution characteristics and possibly even the bioavailability of the drug. REMEDIES : Use of moderate condition of milling. Optimum time of milling .

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EX:- The phase transformation of chloramphenicol palmitate associated with grinding and the effect of seed crystals Form A Form B Form C 16 min. 150 min. 30 min. (1% Form A) 40 min. (1%Form B)

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EFFECT OF COMPRESSION:- O verall amount of energy input into a formulation during compression is not sufficient to induce a phase transformation and for many substances this situation is certainly true.There are numerous examples, for which changes in phase composition do accompany a compression step. Carbamazepine is a drug which shows differences in the dissolution rates that are associated with production of different polymorphs by tablet mfg process. It has 3 different crystalline form – α , β and Dihydrate form.

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EFFECT OF LOCAL MOBILITY :- Local mobility in amorphous forms of pharmaceuticals can lead to changes in their glass transition temperature effect of which is such that amorphous form converts to crystalline form . WET GRANULATION:- Wet granulation process, the both wetting phase solvent and drying phase conditions can cause a suitable environment for the transformation to alternate crystalline forms. API molecule Polymorph 1 Polymorph 2

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REMEDIES : Use of granulating liquid which will not produce polymorphic conversion. Moderate/Optimum condition for drying. Polymorphic transformations during wet granulation can be divided to 1) Conversion of a metastable form to the stable form; 2) Conversion of the stable form to a metastable form; or 3) Conversion of an unsolvate form to a solvate form.

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4 )Microbiological factor Microbial growth in an oral liquid may cause foul odour and turbidity and adversely palatability and appearance. Byproducts of microbial metabolism may cause a change in the pH of the preparation and reduce the chemical stability or solubility of the drug. REMEDIES : Microbial contamination during preparation must minimised by using clean equipment, sterile water (Water for Irrigation BP) and avoiding contaminated raw materials and containers (DRUGS STABILITY, by-Jens T. Carstensen)

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5 )Toxicological factor Water ,vitamins,minerals,enzymes & multitudes of functional groups are present in feed which can severely reduce the shelf life of a drug. (Leon Lachman,Herbert A.Lieberman,Joseph L. Kanig,The theory & Practice of Industrial Pharmacy, Warghese Publication House(Mumbai).)

REFERENCE: 

REFERENCE 1) E.A.Rawlins, Bentley’s Textbook of Pharmaceutics,Bailliere Tindal(2004), 8 th edition, page no-140. 2) Sumie Yoshioka & Valentino J. Stella, Stability of Drugs & Dosage forms, Kluwer Academic Publishers(London), Page No.:3-33. 3) Jens T. Carstensen, Drug stability, Marcel Dekker, 2 nd edition. 4) Patrick J. Sinko, Martin’s Physical Pharmacy & Pharmaceutical sciences, Lippincott Williams & Wilkins, 4 th edition, Page No.:397.

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6) Gilbert S. Banker & Christopher T. Rhodes, Modern Pharmaceutics, Marcel Dekker(New York), 4 th edition. P.K Gupta & S.K Gupta, Pharmaceutics & Cosmetics, Pragati Prakashan(2010), 1 st edition, Page No.:17-22. Alfonso R. Gennaro , Remington: The science & Practice of Pharmacy,Vol-1,Lippincott Williams & Wilkins, 20 th edition-2000,Ch-41, Page No-780. 5) Leon Lachman,Herbert A.Lieberman,Joseph L. Kanig,The theory & Practice of Industrial Pharmacy, Warghese Publication House(Mumbai),3 rd edition, Page No.:171.

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