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Pharm 1st Trimester) Guided by: Dr. Anil Pethe Sir DEPARTMENT OF PHARMACEUTICS NMIMS UNIVERSITY Slide 2: “Always remember that the most important thing in a good marriage is not happiness, but stability.” Drug stability : Drug stability Capability of a particular formulation, in a specific container/closure system, to remain within its physical, chemical, microbiological, therapeutic and toxicological specifications. CHEMICAL ROUTES OF DEGRADATION : CHEMICAL ROUTES OF DEGRADATION Slide 5: Parallel degradation pathways for pralidoxime leading to cyanide formation under basic pH conditions. Slide 6: Dehydration and epimerization of tetracycline, leading to formation of epianhydrotetracycline, known to be associated with Fanconi syndrome Fanconi syndrome Slide 7: Oxidation of epinephrine to the highly colored adrenochrome (adulterated) 1) HYDROLYSIS : 1) HYDROLYSIS The drug comes into contact with water . Hydrolysis is often the main degradation pathway for drug substances having ester and amide functional groups within their structure. ESTERS : ESTERS These ester compounds are primarily hydrolyzed through nucleophilic attack of hydroxide ions. The degradation rate depends on the substituents R1 and R2, in that electron-withdrawing groups (substituted benzoates) enhance hydrolysis whereas electron-donating groups (alkyl group) inhibit hydrolysis. Slide 10: Hydrolysis of a carboxylic acid ester. Slide 11: Lactones, or cyclic esters, also undergo hydrolysis. AMIDES : AMIDES Amide bonds are less susceptible to hydrolysis than ester bonds because the carbonyl carbon of the amide bond is less electrophilic. Slide 13: Hydrolysis of amides Protection against Hydrolysis : Protection against Hydrolysis Removal of water-drug in dry form reconstitute the powder e.G Streptomycin in dry powder for injection Buffers Complexation Suppression of solubility: If solubility decreased ---> conc of drug in soln is decreased ---> hydrolysis is reduced 2) DEHYRATION : 2) DEHYRATION Sugars such as glucose135-137 and lactose138,139 are known to undergo dehydration to form 5(hydroxymethyl)-2-furural. Dehydration of glucose Slide 16: Dehydration of erythromycin 3) ISOMERIZATION : 3) ISOMERIZATION Some drugs have same stuctural formula, but posses different stereochemical configurations. So this interconversion of 1 stereo form into another leads to inactive unstable forms Slide 18: Reported examples of isomerization of drug substances include trans-cis isomerization of amphotericin B (Scheme 33),148 Slide 19: Pilocarpine undergoes epimerization by base catalysis, whereas tetracyclines such as rolitetracycline exhibit epimerization by acid catalysis. 4) RACEMIZATION : 4) RACEMIZATION Racemization of epinephrine Slide 21: Racemization of oxazepam 5) DECARBOXYLATION : 5) DECARBOXYLATION 6) ELIMINATION : 6) ELIMINATION 7) OXIDATION : 7) OXIDATION Oxygen, which participates in most oxidation reactions, is abundant in the environment to which pharmaceuticals are exposed, during either processing or long-term storage Slide 25: Antioxidants such as Tocopherol, BHA(Butylated hydroxy anisole), BHT( butylated hydroxy toluene) 8) PHOTODEGRADATION : 8) PHOTODEGRADATION Photo labile drugs are the drugs which undergo light induced chemical degradation. E.G. conversion of ergosterol to vitamin D by U.V light PHOTODEGRADATION : PHOTODEGRADATION Photodegradation of chloroquine Slide 28: Photochemically induced elimination/hydrolysis. Slide 29: Photooxidation of menadione 9) Polymerization : 9) Polymerization Combination of two or more molecules to form larger molecules Not often the initial cause of drug decomposition Adrenaline Adreno chrome Black brown pigment oxidation polymerise PHYSICAL ROUTES OF DEGRADATION : PHYSICAL ROUTES OF DEGRADATION 1) Loss of volatile constituents: Medicinal agents such as iodine ,camphor, menthol, chloroform have a tendency to evaporate from product during storage. So always keep products in well closed containers and store in cool place 2) Loss of water: decrease in wt ---> increase in conc of drug ---> increase in potency 3) Absorption of water: increase in wt ---> dilutes the dose ---> decrease the potency E.G- Deliquescent substances have a tendency to absorb moisture Slide 32: 4) Crystal growth: SOLUTIONS: If temp is lower ---> soln becomes supersaturated -->ppt and crystallization of drug is observed E.g- 10% w/v calcium gluconate injection is a supersaturated soln. So in order to reduce risk of crystals, I.P suggest use of calcium saccharate( more soluble salt) as a stabiliser SUSPENSIONS: Particles slowly become bigger in size and form a hard cake. Thus blocks hypodermic needle Slide 33: 5) Polymorphism: Cortisone acetate form 2 is more soluble (metastable) but on long storage metastable is converted in to form 4 stable form Amorphous>metastable>stable Slide 34: Metastable form 2 is converted into form 1 i.e stable form on addition of organic solvent aceto nitrile Slide 35: 6) Color change: e.G. 1)aspirin tablets ---> pink in color 2) Ascorbic acid turns yellow 3) Adrenaline on exposure to air turns red 4) Tartrazine tends to fade in presence of additives So always use U.V absorbing substance such as 2,4 dihydro benzophenone Changes in dissolution behavior of nifedipine from amorphous nifidipine samples exposed to different storage conditions : Changes in dissolution behavior of nifedipine from amorphous nifidipine samples exposed to different storage conditions Storage period at 40°C: (1) 0, (2) 3.5, (3) 6 months; (b) storage period at 21°C and 75% RH: (1) 0, (2) 0.5, (3) 1.5, (4) 4 months. Crysatllization of amorphous drugs Amorphous drug Rate of a reaction : Rate of a reaction Law of Mass Action : Law of Mass Action “ According to law of mass action the rate of a chemical reaction is proportional to the product of the molar concentration of the reactants each raised to the power equal to the number of molecules of substances undergoing reaction” Rate process:Law of mass action : Rate process:Law of mass action Law of mass action…. rate is….? 1. CH3COOC2H5 + H2O = CH3COOH + C2H5OH rate? 2. xA + yB → cC + dD rate = k[A]x[B]y (CH3COOC2H5)1 (H2O)1 Slide 41: Rates of reactions can be determined by monitoring the change in concentration of either reactants or products as a function of time. [A] vs. t Slide 42: In this reaction, the concentration of butyl chloride, C4H9Cl, was measured at various times, t. C4H9Cl(aq) + H2O(l) C4H9OH(aq) + HCl(aq) Reaction Rate : Reaction Rate The average rate of the reaction over each interval is the change in concentration divided by the change in time: C4H9Cl(aq) + H2O(l) C4H9OH(aq) + HCl(aq) Slide 44: Reaction Rates Note that the average rate decreases as the reaction proceeds. This is because as the reaction goes forward, there are fewer collisions between reactant molecules. C4H9Cl(aq) + H2O(l) C4H9OH(aq) + HCl(aq) Slide 45: Reaction Rates A plot of concentration vs. time for this reaction yields a curve like this. The slope of a line tangent to the curve at any point is the instantaneous rate at that time. C4H9Cl(aq) + H2O(l) C4H9OH(aq) + HCl(aq) Reaction Rates and Stoichiometry : Reaction Rates and Stoichiometry In this reaction, the ratio of C4H9Cl to C4H9OH is 1:1. Thus, the rate of disappearance of C4H9Cl is the same as the rate of appearance of C4H9OH. C4H9Cl(aq) + H2O(l) C4H9OH(aq) + HCl(aq) Reaction Rates and Stoichiometry : Reaction Rates and Stoichiometry To generalize, for the reaction Reactants (decrease) Products (increase) Rate of reaction : Rate of reaction Reaction rate is the change in the concentration of a reactant or a product with time (dA/dt) d[A] = change in concentration of A over time period Dt d[B] = change in concentration of B over time period Dt Slide 49: Reaction: nX Y We can write the general rate law: Rate Constant Concentration of X Order of reaction Molecularity : Molecularity “number of molecules collide to give product” Unimolar reaction isomerization Bimolecular reaction CH3COOC2H5 + NaOH = CH3COONa + C2H5OH Termolecular reaction Order of reaction : Order of reaction “No. Of Conc. Terms on which rate of reaction depends” Rate = k [A]x[B]y reaction is xth order in A reaction is yth order in B reaction is (x +y)th order overall Slide 53: Order of reaction Zero order “rate doesn't depends on conc term” = k [A]0 = k Integration conc A0 and At A0 - At = kt At = -kt + A0 Unit, Half life and shelf life? Slide 54: Unit: mole/lt.sec Half life: t½ = t when [A] = [A]0/2 Slide 55: First order “rate depends upon conc of one term” rate = k [A]1 ln[A] = ln[A]0 - kt log[A] = log[A]0 – kt/2.303 Unit, Half life and shelf life? Slide 56: Unit: Half life: k = t½ = t when [A] = [A]0/2 = sec-1 Slide 57: Second order “rate depends upon conc of two reactants” rate = k [A]2 Unit, Half life and shelf life? Slide 58: Unit: Half life: k = = lt/Mol•sec t½ = t when [A] = [A]0/2 Effect of Temperature onthe Rates of Reactions : Effect of Temperature onthe Rates of Reactions In 1889, Svante Arrhenius proposed the following expression for the effect of temperature on the rate constant, k = Ae–Ea/RT The constant A, called the frequency factor, is an expression of collision frequency; it represents the number of collisions per unit time. The term e–Ea/RT represents the fraction of molecular collisions sufficiently energetic to produce a reaction. Influence of temperature : Influence of temperature Collision Theory Molecules must collide with the correct orientation and with enough energy to cause bond breakage and formation. Activation Energy : Activation Energy In other words, there is a minimum amount of energy required for reaction: the activation energy, Ea. Just as a ball cannot get over a hill if it does not roll up the hill with enough energy, a reaction cannot occur unless the molecules possess sufficient energy to get over the activation energy barrier. The Arrhenius Equation : The Arrhenius Equation 1903 Nobel Prize citation” …in recognition of the extraordinary services he has rendered to the advancement of chemistry by his electrolytic theory of dissociation” The temperature dependence of the rate constant k is best described by the Arrhenius equation: Ea 2.303 R T log k = log A – Sometimes log t1/2 is taken instead of log k 1st order: t1/2 0.693 / k Ea 2.303 R T log t1/2 = C + k, specific rate cons A, frequency or Arrhenius factor (const.) Ea, energy of activation T, absolute temp R, gas const. Ea = 2.303 R T1 T2 (T2 – T1) log k2 k1 ln k = ln A – Ea / R T k = A e – Ea / R T Slide 65: Arrhenius Equation Taking the natural logarithm of both sides, the equation becomes y = mx + b When k is determined experimentally at several temperatures, Ea can be calculated from the slope of a plot of ln k vs. 1/T. Slide 66: Ea 2.303 R T log k = log A – 400C 500C 600C 700C Conc remained time 70 60 50 40 25 log k 1/T 70 60 50 40 25 1/T % drug remaining Q10 Calculations : Q10 Calculations Connors et al. described a straightforward calculation that facilitates a practical understanding of temperature effects Using this method the effect of 100 rise in temperature on the stability of pharmaceuticals can be estimated. Q10=k (T+10) /kT Q10 Calculations : Q10 Calculations Q10 is a factor by which the rate constant increases for a 100C temperature increase. The Q10 factor can be calculated from the following equation: Methods for detecting chemical and physical degradation : Methods for detecting chemical and physical degradation DSC : DSC Calorimetric changes and wt changes caused by physical and chemical degradation of drugs can be easily detected by DSC. E.G Poorly water soluble drug alpha pentyl 3-(2-quinolinyl methoxy)benzemethanol(REV5901). The free base exhibited an endothermic peak due to melting that was observed at the same position regardless of storage and measurement conditions. On the other hand, the anhydrous and monohydrate hydrochloride salt forms showed different behaviors depending on measurement conditions. The free base was found to be more physically stable than the hydrochloride salt. Based on these results, the free base was chosen for formulation. Slide 71: REV5901 free base (1) showed no significant change with changes in atmospheric conditions. anhydrous hydrochloride salt on an open pan without purging with N2 (2), in a pan closed by crimping (3), and in a hermetically sealed pan (4) and for the monohydrate hydrochloride salt on an open pan without purging with N2 (5), on an open pan with purging with N2 (6), in a pan closed by crimping (7) and in a hermetically sealed pan (8). (A) Dehydration; (B) melting endotherms. Slide 72: Thermal analysis is often capable of easily detecting drug-excipient interactions. Interaction of ibuprofen with magnesium oxide was detected from changes in DSC thermograms Slide 73: DSC thermograms showing the interaction between ibuprofen and magnesium oxide. (1:1 mixture). (a) Before storage; (b) after 1-day storage at 55°C Change of interaction due to storage measured by DSC Slide 74: A natural logarithm plot of heat changes with time produced during the hydrolysis of aspirin at Ph 1.1 and 45°C. Heat flow produced from the hydrolysis of aspirin in acidic solution decreased according to first-order kinetics indicating that degradation can be measured by microcalorimetry. DECREASED HEAT FLOW MEASURED BY MICROCALORIMETRY Slide 75: The rate constants determined by microcalorimetry were consistent with those extrapolated from the rate constants determined by HPLC. Arrhenius plots of the oxidation rate constant of α -tocopherol measured by microcalorimetry (o) and HPLC (∆). RESULTS BT HPLC AND MICROCALORIMETRY ARE SAME Diffuse reflectance spectroscopy : Diffuse reflectance spectroscopy Diffuse reflectance spectroscopy (DRS), established by Kortum and co-workers was employed to detect the solid-state interactions. The DRS spectrum of an isoniazid-magnesium oxide mixture exhibited a decrease in reflectance r∞ with increasing isoniazid content. Slide 77: Diffuse reflectance spectroscopy of isoniazid-magnesium oxide mixtures. Isoniazid concentration (mg/g of MgO): (A) 3, (B) 7, (C) 10, (D) 13, (E) 16. DECREASE IN REFLECTANCE WITH INCREASED ISONIAZID CONC. Slide 78: FUNCTIONAL CHANGES IN DOSAGE FORMS WITH TIME Changes in mechanical strength : Changes in mechanical strength Moisture adsorption (a) and strength change (b) of model tablets stored in blister packages maintained at 21-22°Cand varying relative humidities. ,▪ 25% RH, , □60% RH; ,● 70% RH; , ◦95% RH. INCREASES DECREASES Changes in dissolution rate of carbamazepine tablets during storage : Changes in dissolution rate of carbamazepine tablets during storage ●Before storage; ∆, after 6-day ◊ dried at 85°C after 6-day storage at 100% RH. DECREASES DECREASES DECREASES Changes in nitrofurabtoin excretion rate from nitrofurantoin capsules containing different amount of carbomer stored under different conditions : Changes in nitrofurabtoin excretion rate from nitrofurantoin capsules containing different amount of carbomer stored under different conditions Before storage; ▪formulation containing less carbomer after I-year storage at 40°C and 30% RH; ●formulation containing more carbomer after 1-year storage at 40°C and 60% RH. DECREASES Changes in the swelling force of alginic acid (decreases) : Changes in the swelling force of alginic acid (decreases) Changes in the swelling force of alginic acid after one-year storage under a variety of conditions. Before storage. Storage conditions: +, 25°C; x, 30°C; 30°C and 75% RH; ∆, 40°C; 50°C. Changes in the dissolution rate of enteric coated aspirin tablets (decreases) : Changes in the dissolution rate of enteric coated aspirin tablets (decreases) Changes in the dissolution rate of enteric-coated aspirin tablets after storage. The curves represent the dissolution rates before storage (o) and after storage at 33°C and 60% RH for 10(▪) 20(◊) and 42(●_) days Chloramphenicol capsules (decreases) : Chloramphenicol capsules (decreases) Changes in the dissolution rate of two different chloramphenicol capsules at 49% RH (a) and 66% RH (b). The curves represent the dissolution rates before storage ( x) and after storage for 2 (●), 8(o) and 16 weeks (∆). Changes in melting time of suppositories : Changes in melting time of suppositories Changes in the melting time of suppositories following storage at 20°C. Change in droplet size of emulsions : Change in droplet size of emulsions Changes in the droplet size of emulsions with time at 4°C Drug leakage from liposomes : Drug leakage from liposomes Effect of membrane components on the leakage of 5-fluorouracil from liposomes during storage at 4°C. (O)LUV (PC/PS/CH 7:4:5); ∆, LUV (MC/PS/CH 7:4:5); □MLV (PC/PS/CH 7:4:5). STORAGE CONDITIONS : STORAGE CONDITIONS COLD PLACE: Not exceeding 8*C COOL PLACE: 8-25*C Warm temp: 30-40*C Excessive heat: >40*C Controlled room temp : 20-25*C (Not prescribed by I.P., but prescribed by USP 23,1995) Freezer: Temp between -29*C and -10*C CONCLUSION : CONCLUSION Initially the whole world was facing a real problem of drugs stability. Stability of drugs is a major problem especially for new molecules which are being synthesized. Slide 90: Initially not much concern and attention was given to medicines and capsules and thus various unwanted and undesired disasters were occurring, and money was given more concern. Slide 91: But due to tremendous development in research and development day by day, scientists, doctors and patients will not have to worry about stability problems ……… Please don’t wory,i m stable You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.