stability studies

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kinetics of decomposition, accelerated stability studies, freeze thawing methods.

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Kinetics and Drug Stability Under the Guidance of Dr.R.Santosh Kumar, M.Pharm, Ph.D. :

Kinetics and Drug Stability Under the Guidance of Dr.R.Santosh Kumar , M.Pharm, Ph.D. K.P.R.R.Sekhar Reg.No:611233701033 M.Pharmacy, Dept. of Pharmaceutical Technology SrinivasaRao College of Pharmacy.

Definition :

Definition Stability is defined as the capacity of a drug substance to remain within the established specifications to maintain its identity, strength , quality and purity throughout the retest or expiration dating period. 2

Stability :

Stability 3

Importance :

Importance The primary reason for stability testing is the concern for the well-being of the patient suffering from the disease for which the products is designed. Second important concern is to protect the reputation of the manufacturer. 4

Purpose :

Purpose Stability testing is used to Provide evidence as to how the quality of the drug product varies with time under the influence of variety of environmental factors. Establish shelf life for the drug product Determine recommended storage conditions Determine container closure system suitability. 5

KINETICS :

KINETICS Kinetics is the study of the rate at which processes occur. It is useful in providing information that: a) Gives an insight into the mechanisms of changes involved, and b)Allows a prediction of the degree of the change that will occur after a given time has elapsed. 6

ZERO ORDER REACTION :

ZERO ORDER REACTION Zero order reaction is defined as a reaction in which the rate does not depend on the concentration terms of the reactants. This is mathematically expressed as: -dc/dt = k o where k o is the specific rate constant for a zero order. E.g. colour loss of liquid multisulfonamide preparation. colour loss is proportional to decrease in the concentration 7

ZERO ORDER REACTION :

ZERO ORDER REACTION The rate constant can be calculated by k 0 = (a-c)/t Half life can be calculated by using t 1/2 = (a-c)/k 0 = a/2k 0 Shelf life can be calculated by using t 90 = (a – 0.9a)/k 0 = 0.1a/k 0 8

First order reaction:

First order reaction First order reaction is defined as the reaction in which the rate of reaction depends on the concentration of one reactant. The first order reaction can be written as -dc/dt α c -dc/dt = k 1 c Where c is the concentration of the reactant and k1 is the specific rate constant for first order. 9

First order reaction:

First order reaction First order rate constant can be calculated using k 1 = 2.303 log c o t c t half life can be calculated using t 1/2 = 0.693/k 1 shelf life can be calculated using t 90 = 0.105/k 1 10

Second order reaction:

Second order reaction First order reaction is defined as the reaction in which the rate of reaction depends on the concentration terms of two reactants each raised to the power one. A + B products The reaction rate can be written as -dA = -dB = k 2 [A] 1 [B] 1 dt dt 11

Apparent zero order :

Apparent zero order Pseudo zero order is a reaction which may be a first order, but behaves like a zero order, depending on the experimental conditions. E.g. Suspensions follow pseudo zero order Solid state decomposition . The rate equation can be written as -d[A]/dt = k 1 × constant = k 0 12

Pseudo first order reaction:

Pseudo first order reaction Pseudo first order reaction is defined as a reaction which is originally a second order but is made to behave like a first order reaction. E.g. Hydrolysis of ester acid catalysed hydrolysis of digoxin. The rate equation can be written as -dc/dt = k 2 [A][constant] = k 1 [A] 13

Kinetics of drug decomposition:

Kinetics of drug decomposition A drug in suspension follows apparent zero-order kinetics in which the concentration of the drug in the solution remains constant with time. When the drug in the solution degrades or lost by any means new drug molecules from the suspended solid particles dissolve in the solution to keep the concentration constant at the equilibrium solubility. That is the solid suspended particles acts as reservoir of drug. 14

Kinetics of drug decomposition:

Kinetics of drug decomposition Photochemical degradation of chlorpromazine in aqueous solution follows zero order where the degradation of the chlorpromazine does not depends upon the concentration of the drug. oxidation of vitamin A in an oily solution follows zero order and the degradation of the vitamin A does not depends upon the concentration of the drug but depends upon the amount of the oxygen. 15

Kinetics of drug decomposition:

Kinetics of drug decomposition Acid catalysed hydrolysis of digoxin follows pseudo first order reaction kinetics, here the concentration of H+ ions remains constant. Therefore the rate solely depends on the concentration of the digoxin. Hydrolysis of chlorbutanol in presence of sodium hydroxide follows second order reaction . 16

Effect of various factors on the stability:

Effect of various factors on the stability BLENDING/MIXING Most important step for manufacturing of dosage form. High speed - introduce air into the product Slow speed- not form a satisfactory product. During mixing other factors like type of agitator , temperature or vaccum etc. can affect the stability. Electrostatic charges generate due to particle-particle and particle wall collision. 17

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Eg.- during mixing, if vacuum is not applied than air bubble will present into the product that produce oxidation of product. Ways for stabilization Use of optimum time and rate of mixing. Use of optimum and controlled temperature. Application of vacuum. Use of closed system. 18

FREEZE-DRYING PROCESS:

FREEZE-DRYING PROCESS Either increase or decrease in the stability. To produce physically stable formulation. Applicable for multivitamin preparation, antibiotics, hormones and proteins formulation. Cryoprotectant is added, when product is lyophilized. 19

FREEZE-DRYING PROCESS:

FREEZE-DRYING PROCESS To act successfully as a protectant, it should have, A high glass transition temperature (T g ), A poor hygroscopicity, A low crystallization rate, Contain no reducing groups. 20

TEMPERATURE :

TEMPERATURE Primary factor affecting the drug stability. To study the effect of temperature on reaction, it is necessary to study decomposition of product at elevated temperature. Help in predicting stability of product at ordinary temperature. 21

Temperature :

Temperature Ways for stabilization: Product should be stored within the temperature range in which they are stable. They should be exposed to extremes of temperature. Few drugs which has adverse effects on freezing, so for that drug freezing should be avoided unless until it is stable at such temperature. 22

HUMIDITY :

HUMIDITY Higher humidity may leads to moisture adsorption. Drugs which are highly sensitive to hydrolysis Relative humidity Stability increase decrease 23

Humidity :

Humidity It can affect the stability of product by, Hydrolytic degradation Isomerisation Crystallization Flow property Ways for stabilization Maintenance of controlled humidity condition. Moisture proof packing. 24

pH :

pH By changing 1 pH unit , there is change in more than 10 fold in rate constant. Before formulating drug in solution, K vs pH should be studied and optimum pH at lowest value of rate constant is to be found. Hydrogen ion catalysis occurs at lower pH, Hydroxyl ion occurs at higher pH. Ways for stabilization Maintenance of stable pH by use of appropriate buffer salts. 25

EFFECT OF SOLUBILITY :

EFFECT OF SOLUBILITY Applicable to drugs in solution form. Eg :- Penicillin are very unstable in aqueous solution because of hydrolysis of β- lactum ring. Ways for stabilization Stabilized by using insoluble salts of API. Formulate the drug in suspension dosage form. 26

PROTECTION AGAINST HYDROLYSIS:

PROTECTION AGAINST HYDROLYSIS Good packaging practices like moisture resistant packs. Eg- strip packs stored in controlled humidity and temperature conditions, even using desiccant such as silica gel. Buffering agents for pH control Alteration of dielectric constant Addition of complexing agents like caffeine Use of Surfactants ,Good Refrigeration 27

PROTECTION AGAINST OXIDATION:

PROTECTION AGAINST OXIDATION Incorporation of antioxidants such as BHA, BHT, Propyl gallate, Tocopherol Chelating using EDTA, Citric acid, Tartaric acid Use of inert gas like Nitrogen Protection from light by use of amber colored container Storage at low temperature 28

What are the changes?:

What are the changes? A drug substance, which is not of sufficient stability, can result in changes in physical characteristics appearance, melting point, clarity and colour of solution, crystal modification (polymorphism) particle size 29

What are the changes?:

What are the changes? Chemical characteristics increase in impurities and decrease in assay Microbiological attributes Total bacterial count, fungal count and for pathogenic microbes. 30

DRUG STABILITY:

DRUG STABILITY The stability of pharmaceutical product is investigated throughout the various stages of the development process. The stability of the drug substance is first assessed in the preformulation stage. Stability/ compatibility with various solvents, buffered solutions, and excipients considered for formulation developments 31

Where and Why?:

Where and Why? Stability Studies are preformed on ... Drug Substances (DS)  The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form. Drug Products (DP)  The dosage form in the final immediate packaging intended for marketing. 32

Stability Protocol:

Stability Protocol Batch selection Container Closure System Specifications Testing frequency Storage conditions Sample Quantity Statements and labelling Stability commitment 33

Batch Selection:

Batch Selection Three Primary batches of drug substance are to be kept for stability studies. Usually three commercial batches to be kept in studies and the batches may be first three batches. One add-on batch for every year. This might be the first batch of that year. 34

Container Closure System: :

Container Closure System: Container Closure System Stability Studies to be conducted in the container closures that are similar to the containers in which the Drug substance is marketing. For example, Itraconazole is stored in transparent polyethylene bag[primary packing] and which in turn stored in black polyethylene bag and finally in HDPE container [secondary packing]. 35

Specification:

Specification Specification Stability analysis is performed for the test parameters which are prone to change during the storage and are likely to influence the Quality, safety and Efficacy 36

Testing frequency :

Testing frequency For long term testing during 1 st year sampling should be done every 3 months, during 2 nd year sampling should be done every 6 months and after two years sampling should be done once a year. Accelerate testing should be done at least 6 months and it suggests sampling points of 0,3,6 months. 37

Types of Stability Studies :

Types of Stability Studies As described by the ICH, stability testing provides evidence of the effect of time and environmental factors on the quality of pharmaceuticals and also to establish a re-test period for the drug substance along with recommended storage conditions. So these studies are very important 38

Types of stability studies:

Types of stability studies Stability studies are classified into three types, based the temperature and Humidity employed during the studies. These are: long term stability studies Intermediate stability studies Accelerated stability studies 39

Long Term Studies::

Long Term Studies: Long term stability studies are conducted under the recommended storage condition for the re-test period proposed (or approved) for labelling and assigning the retest period. E.g. 25°C/60%RH for normal storage conditions and  5°C for refrigerated storage conditions 40

Intermediate testing:

Intermediate testing Intermediate studies are conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance intended to be stored long term at 25°C. Generally these studies are conducted when the accelerated studies for General Case (40°C/75 %RH ) falied to meet the acceptance criteria. 41

Accelerated Studies:

Accelerated Studies These studies are conducted at a) 40°C/75%RH for normal storage conditions [25+/-2°C and 60+/-5%RH] b) 25°C/60%RH for refrigerated storage conditions[5+/-3°C]. 42

Accelerated studies:

Accelerated studies Accelerated Studies are designed to increase the rate of chemical degradation or physical change of a drug substance  by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping 43

General case:

General case Study Storage conditions Minimum time period covered by data at submission Long term (ambient) 25 o C±2 o C 60%RH±5% 12 months Intermediate (controlled) 30 o C±2 o C 60%RH±5% 6 months accelerated 40 o C±2 o C 75%RH±5% 6 months 44

Active substances intended for storage in a refrigerator:

Active substances intended for storage in a refrigerator Study Storage condition Minimum time period covered by data at submission Long term 5°C ± 3°C 12 months Accelerated* 25°C ± 2°C / 60% RH ± 5% RH or 30°C ± 2°C / 65% RH ± 5% RH 6 months 45

Active substances intended for storage in a freezer:

Active substances intended for storage in a freezer Study Storage condition Minimum time period covered by data at submission Long term - 20°C ± 5°C 12 months 46

Testing frequency :

Testing frequency For long term testing during 1 st year sampling should be done every 3 months, during 2 nd year sampling should be done every 6 months and after two years sampling should be done once a year. Accelerate testing should be done at least 6 months and it suggests sampling points of 0,3,6 months. 47

Accelerated stability studies:

Accelerated stability studies Stability studies to predict the shelf life of the product by accelerating the rate of decomposition preferably by increasing the temperature of reaction conditions. With the advancement in branch of kinetics shelf life of a dosage form can be predicted within moths based on accelerated stability reports. 48

Accelerated stability studies:

Accelerated stability studies Preparations are subjected to high stress during stability testing. common high stresses include Temperature Humidity light 49

Arrhenius equation:

Arrhenius equation The Arrhenius equation is the one which explains the temperature dependence of the reaction rate constant, and therefore, rate of a chemical reaction. The equation was first proposed by the Dutch chemist J. H. van 't Hoff in 1884; five years later in 1889, the Swedish chemist Svante Arrhenius provided a physical justification and interpretation for it. 50

Arrhenius equation:

Arrhenius equation At higher temperatures, the probability that two molecules will collide is higher. This higher collision rate results in a higher kinetic energy, which has an effect on the activation energy of the reaction. The activation energy is the amount of energy required to ensure that a reaction happens. 51

Arrhenius equation:

Arrhenius equation According to Arrhenius, for every 10 o rise in temperature the speed of reaction increases about 2-3 times. K = Ae -Ea/RT or ln K = - Ea/RT + ln A Where , A= Arrhenius factor e = energy of activation R= ideal gas constant T= absolute temperature 52

Arrhenius equation:

Arrhenius equation Arrhenius factor is the frequency of molecular collisions occurring between the molecules. ln K = - Ea/RT + ln A logk = logA – Ea/2.303RT 53

Arrhenius equation:

Arrhenius equation After observing that many chemical reaction rates depended on the temperature, Arrhenius developed this equation to characterize the temperature-dependent reactions. The Factors K : Chemical reaction rate and is unit of s -1 (for 1st order rate constant) or M -1 s -1 (for 2nd order rate constant) 54

Arrhenius equation:

Arrhenius equation A is pre-exponential factor  or frequency factor and is related to molecular collisions. Deals with the frequency of molecules that collide in the correct orientation and with enough energy to initiate a reaction. It is a factor that is determined experimentally, as it varies with different reactions. 55

Arrhenius equation:

Arrhenius equation In unit of Lmol -1 s -1 or M -1 s -1 (for 2 nd order rate constant) and s -1 (for 1 st order rate constant). Because frequency factor A is related to molecular collision, it is temperature dependent 56

Arrhenius equation:

Arrhenius equation E a: The activation energy is the threshold energy that the reactant(s) must acquire before reaching the transition state. Once in the transition state, the reaction can go in the forward direction towards product(s), or in the opposite direction towards reactant(s). 57

Arrhenius equation:

Arrhenius equation A reaction with a large activation energy requires much more energy to reach the transition state. Likewise, a reaction with a small activation energy doesn't require as much energy to reach the transition state. In unit of kJ/mol. -Ea/RT resembles the Boltzmann distribution law. 58

Arrhenius equation:

Arrhenius equation R: The gas constant . Its value is 8.314 J/mol K. T: The absolute temperature  at which the reaction takes place. In units of Kelvin (K). 59

Application of Arrhenius equation:

Application of Arrhenius equation Application of the Arrhenius equation in pharmaceutical stability testing is straightforward. In the isothermal method, the system to be investigated is stored under several high temperatures with all other conditions  fixed. Excess thermal exposure accelerates the degradation and thus allows the rate constants to be determined in a shorter time period. 60

Arrhenius equation:

Arrhenius equation Most accelerated testing models are based on the Arrhenius equation where k2 and k1 are rate constants at temperature T2 and T1 , respectively; Ea is the activation energy; and R is the gas constant. Temperature is in Kelvin. 61

Arrhenius equation:

Arrhenius equation This equation describes the relationship between storage temperature and degradation rate. Use of the Arrhenius equation permits a projection of stability from the degradation rates observed at high temperatures. Activation energy, the independent variable in the equation, is equal to the energy barrier that must be exceeded for the degradation reaction to occur. When the activation energy is known (or assumed), the degradation rate at low temperatures may be projected from those observed at “stress” temperatures. 62

Estimation of k value :

Estimation of k value The reaction is conducted at several temperatures. Concentration of the reactants is determined. Appropriate graphs are drawn for the kinetic data. Data is processed for all the orders. The order of reaction is identified. From the slopes of the line , k values are calculated for all the temperatures. 63

Estimation of energy of activation:

Estimation of energy of activation Activation energy is the minimum energy that a molecule should possess so that the molecular collisions produce the product. A graph can be drawn by taking logk on y-axis and 1/T on x-axis. A straight line is obtained, the slope of the line is negative and the magnitude is Ea/2.303R. The intercept correspond to logA. All constants in the Arrhenius equation can be obtained from the graph. 64

Estimation of energy of activation:

Estimation of energy of activation The intercept correspond to logA. All constants in the Arrhenius equation can be obtained from the graph. 65

Steps involved in prediction of shelf life:

Steps involved in prediction of shelf life The preparation is stored at different elevated temperatures to accelerate the degradation. Samples are withdrawn at different time intervals. The order of the reaction is determined by plotting the appropriate function of concentration against time and linear relationship is determined. 66

Steps involved in prediction of shelf life:

Steps involved in prediction of shelf life Straight line in a graph permits the estimation of k value from the slope. Similarly graphs are drawn for different elevated temperatures. K values for each temperature are calculated. By using Arrhenius relationship logK values are plotted against reciprocals of absolute temperature, energy of activation can be calculated. 67

Steps involved in prediction of shelf life:

Steps involved in prediction of shelf life Extrapolate the straight line to room temperature (K 25 ) or refrigerated temperature and read the logK value on Y- axis. Substitute the K value in the appropriate equation to get the shelf life of the product. 68

Accelerated stability testing in emulsions:

Accelerated stability testing in emulsions An emulsion is stored at elevated temperature. If the emulsion withstands this stress it is assumed to be stable at normal conditions of storage. 69

Centrifugation method :

Centrifugation method Creaming and flocculation are slow process. Centrifugation accelerates rates of creaming and flocculation in emulsion. The emulsion is subjected to different centrifugal speeds and separation of phases is observed at different time periods. 70

Centrifugation method:

Centrifugation method Bad emulsion separates oil instantly. Good emulsion does not exhibit detectable separation of oil phase until certain time period. 71

Accelerated tests for suspensions:

Accelerated tests for suspensions Cake formation is accelerated by centrifugation. High speed centrifugation is hence not preferred, low speed centrifugation is used to study the physical stability. 72

Accelerated test for moisture absorption:

Accelerated test for moisture absorption In this methods, products are placed in a an environment of high relative humidity and controlled temperature. Their physical and chemical stabilities are assessed. The results will indicate whether the product is susceptible to moisture and also whether the container needs to provide a high degree of protection. 73

Limitations :

Limitations Stability predictions based on Arrhenius equation are valid only when the break down depends on temperature. The energy of activation obtained in the study should be between 10 to 30 K.cal/ mole. When degradation is due to microbial contamination, photochemical reaction. 74

Arrhenius equation:

Arrhenius equation When the product looses its physical integrity at higher temperature. In case of disperse systems, when temperature is elevated viscosity is decreased and this may introduce errors in the prediction of stability. 75

Freeze thaw testing:

Freeze thaw testing 76

What is Freeze Thaw testing? :

What is Freeze Thaw testing? Freeze thaw testing is a type of stability test in which you freeze your formula, then thaw it out , and test to see what effect the process has on your product. To do a thorough freeze-thaw test you will repeat the cycle a few times. 77

Freeze thaw testing:

Freeze thaw testing Freeze thaw testing gives you information that regular stability testing can’t. Namely, it will show you whether your formula will remain stable under varied conditions that it might experience during the shipping and storage phases of the product life cycle. 78

Freeze thaw testing:

Freeze thaw testing It’s likely that your product will be shipped via trucks or rail cars. These vehicles are rarely equipped with temperature controls so it is likely that your product may freeze one day and be in hot temperatures another. It is crucial that your formula is able to withstand extreme, rapid temperature changes. 79

How to conduct a freeze-thaw test? :

How to conduct a freeze-thaw test? While there is no “right” way to do a freeze-thaw test, the following method is standard in the industry. Step 1 – Prepare samples. (3 test, 1 control) Step 2 – Take initial readings. Step 3 – Put test samples in the freezer for 24 hours Step 4 – Remove samples and allow to thaw at room temperature Step 5 - Put samples in 50C oven for 24 hours Step 6 – Remove samples & allow to equilibrate at room temperature. Step 7 – Take end of the cycle readings 80

Freeze thaw testing:

Freeze thaw testing 81

Freeze thaw testing:

Freeze thaw testing You should repeat this test through 3 cycles. If done correctly it can be completed in 3 weeks. 82

What to look for? :

What to look for? While the specific tests will depend on the type of formula you are testing, generally you’ll want to take readings for Appearance, Odour, Viscosity and pH. Make particular note of whether there is any separating at the top or the bottom of samples. This is the most common form of instability. You may also test the products for performance characteristics just to ensure that the formulas still work as expected. 83

Stability Specifications [Drug Product]:

Stability Specifications [Drug Product] A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests. 84

Stability Specifications :

Stability Specifications Stability studies should include testing of those attributes of the drug product that are susceptible to change during  storage and are likely to influence quality, safety, and/or efficacy. 85

Stability Specifications :

Stability Specifications The testing should cover the following attributes Physical – Appearance, Friability, Uniformity of Dosage Units(uniformity of mass), Hardness, Particulate Matter Chemical - Assay, Degradation Products, Uniformity of Dosage Units (Content Uniformity) 86

Stability Specifications :

Stability Specifications Microbiological attributes - - Total Aerobic Bacterial Count, - Total Fungal Count, Pathogens- Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Salmonella. Endotoxin test, Sterility test, 87

Stability Specifications :

Stability Specifications Preservative content –Antioxidant(this test may be required for Liquid orals), antimicrobial preservative (This test may be required for oral liquids(suspensions and liquids), injecatables. and Functionality tests -for a dose delivery system. 88

Stability Specifications for Tablets and Capsule Dosage forms :

Stability Specifications for Tablets and Capsule Dosage forms Description Identification Friability Hardness LOD/Water Content Uniformity of Dosage Units (uniformity of content or uniformity of mass) Dissolution Disintegration Assay Degradation Products 89

Stability Specifications for Parentral Dosage forms :

Stability Specifications for Parentral Dosage forms Description Identification pH Uniformity of dosage units Particulate Matter Assay Degradation Products Antimicrobial Preservative Content Endotoxin Test / Pyrogens test Sterility test 90

Stability Specifications for liquid Oral Dosage forms :

Stability Specifications for liquid Oral Dosage forms Description Identification Uniformity of dosage units pH Relative Density Assay Degradation Products Antioxidant content Antimicrobial Preservative Content 91

Emulsion properties to be monitored during stability testing:

Emulsion properties to be monitored during stability testing 92

Commonly used test conditions for emulsion stability testing:

Commonly used test conditions for emulsion stability testing 93

Codes and titles used in ICH Guidelines :

Codes and titles used in ICH Guidelines 94 Quality topic of ICH consists of six sub-topic as follows: Q1: Stability testing Q2 : Analytical method validation Q3 : Impurity testing Q4 : Pharmacopoeial harmonization Q5 : Quality of Bio-technological products Q6 : Specification for new drug substance and drug products

Temperature and humidity control:

Temperature and humidity control Temperature and humidity can be controlled by using HVAC system. 95

Conclusion :

Conclusion Stability testing is now the key procedural component in the pharmaceutical development program for a new drug as well as new formulation. Stability tests are carried out so that recommended storage conditions and shelf life can be included on the label to ensure that the medicine is safe and effective throughout its shelf life. 96

Conclusion :

Conclusion Over a period of time and with increasing experience and attention, the regulatory requirements have been made increasingly stringent to achieve the above goal in all possible conditions to which the product might be subjected during its shelf life. Therefore, the stability tests should be carried out following proper scientific principles and after understanding of the current regulatory requirements and as per the climatic zone. 97

References :

References ICH Q1A(R2). Stability testing guidelines : Stability testing of new drug substances and products. ICH Steering Committee, 2003. Stability testing of pharmaceutical products, a review by Sanjay Bajaj, Dinesh Singla and Neha Sakhuja. The theory and practice of industrial pharmacy, Lachman and libermann . Text book of physical pharmacy by matin. 98

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