Colloidal Dispersion PDF

PPAR Lecture | FINALS Because of their size, colloidal particles may be separated from molecule and ion particles by dialysis...

PPAR Lecture | FINALS Because of their size, colloidal particles may be separated from molecule and ion particles by dialysis Topic Outline: ○ dialysis – removes LMW (low molecular weight) impurities Topic I - Colloidal Dispersion in the blood of the patient Through the semi permeable membrane of collodion or cellophane, the small molecules and ions of urea, glucose and NaCl can pass COLLOIDAL DISPERSION through the pore size that prevents the passage of colloidal particles. DISPERSED SYSTEMS ULTRAFILTRATION Dispersed particles (dispersed phase) = discontinuous / internal Used to separate and purify colloidal material; this can be Dispersing medium (dispersing phase) = continuous / external conducted under negative pressure (suction) through a dialysis membrane supported in a Buchner Funnel. CLASSIFICATION OF DISPERSED SYSTEM Ultrafiltration membranes have a pore size between 1 nm and 100 1. True Solutions is defined as a mixture of two nm or more components that form a homogenous molecular dispersion or one-phase system Ex: glucose, oxygen and ordinary ions particle size very strong relationship 0.6 ≤ |r| < 0.8 => strong relationship 0.4 ≤ |r| < 0.6 => moderate relationship 0.2 ≤ |r| < 0.4 => weak relationship 0.0 ≤ |r| < 0.2 => very weak relationship …where |r| (read “the modulus of r”) is the absolute (non-negative) value of r.  One can test whether r is statistically significantly different from zero (the value of no correlation). Note that the larger the sample the smaller the value of r that becomes significant. For example, with n=10 paired observations, r is significant if it is greater than 0.63. With n=100 pairs, r is significant if it is greater than 0.20. The square of the correlation coefficient (r2) indicates how much of the variation in variable y is accounted for (or “explained”) by the variable x. For example, if r = 0.7, then r2 = 0.49, which suggests that 49% of the variation in y is explained by x. Important Points: 1.Correlation only measures linear association. A U-shaped relationship may have a correlation of zero. 2. It is symmetric about the variables x and y - the correlation of (x and y) is the same as the correlation of (y and x). 3. A significant correlation between two variables does not necessarily mean they are causally related. 4. For large samples very weak relationships can be detected. Simple Linear Regression Simple linear regression is used to describe the relationship between two variables where one variable (the dependent variable, denoted by y) is expected to change as the other one (independent, explanatory or predictor variable, denoted by x) changes. This technique fits a straight line to data, where this so-called “regression line” has an equation of the form: y = a + bx a = constant (y intercept) b = gradient (regression coefficient) y = value of dependent variable (y axis) x = value of independent variable (x axis) The model is fitted by choosing a and b such that the sum of the squares of the prediction errors (the difference between the observed y values and the values predicted by the regression equation) is minimized. This is known as the method of least squares. The method produces an estimate for b, together with a standard error and confidence interval. From this, one can test the statistical significance of b. In this case, the null hypothesis is that b = 0, i.e. that the variation in y is not predicted by x. The regression coefficient b tells us that for every 1 unit change in x (explanatory variable) y (the response variable) changes by an average of b units. Note that the constant value a gives the predicted value of y when x = 0. Important Points: 1. The relationship is assumed to be linear, which means that as x increases by a unit amount, y increases by a fixed amount, irrespective of the initial value of x. 2. The variability of the error is assumed not to vary with x (homoscedasticity). 3. Unlike correlation, the relationship is not symmetric, so one would get a different equation if one exchanged the dependent and independent variables, unless all the observations fell on the perfect straight line y = x. 4. The significance test for b yields the same P value as the significance test for the correlation coefficient r. 5. A statistically significant regression coefficient does not imply a causal relationship between y and x.  Correlation coefficient The degree of association is measured by a correlation coefficient, denoted by r. It is sometimes called Pearson's correlation coefficient after its originator and is a measure of linear association. If a curved line is needed to express the relationship, other and more complicated measures of the correlation must be used. The correlation coefficient is measured on a scale that varies from + 1 through 0 to - 1. Complete correlation between two variables is expressed by either + 1 or -1. When one variable increases as the other increases the correlation is positive; when one decreases as the other increases it is negative. Complete absence of correlation is represented by 0.  Significance Test To test whether the association is merely apparent, and might have arisen by chance use the t test in the following calculation: The t is entered at n - 2 degrees of freedom. For example, the correlation coefficient for these data was 0.846. The number of pairs of observations was 15. Spearman rank correlation A plot of the data may reveal outlying points well away from the main body of the data, which could unduly influence the calculation of the correlation coefficient. Alternatively the variables may be quantitative discrete such as a mole count, or ordered categorical such as a pain score. A non-parametric procedure, due to Spearman, is to replace the observations by their ranks in the calculation of the correlation coefficient. This results in a simple formula for Spearman's rank correlation, Rho. where d is the difference in the ranks of the two variables for a given individual.  CHEMICAL KINETICS - is the study of the rates of reactions and the mechanism by which these reactions occurs Rate of a reaction- refers to the velocity of which the reaction occurs. Order of a reaction- refers to the way in which the concentration of a drug or reactant in a chemical reaction affects the rate. PARAMETER SYMBOL UNIT EXAMPLE RATE Dd/dt Mass/time mg/hr ZERO ORDER Ko Concentration/time ug/mL/hr CONSTANT Mass/time FIRST ORDER K Concentration/time 1/hr or hr- CONSTANT DRUG DOSE Do Mass Mg CONCENTRATION C Mass/volume ug/mL VOLUME V Volume mL or L AREA UNDER THE AUC Concentration x ug-hr /mL CURVE time FRACTION OF DRUG F No unit 0 to 1 ABSORBED CLEARANCE Cl Volume/time mL/hr HALF-LIFE t1/2 Time Hr  ZERO ORDER FIRST ORDER RATE CONSTANT Ko K Constant amount per Constant Fraction per unit time unit time independent on dependent on concentration of concentration of reactant reactant Concentration vs Time Linear graph Hyperbola Examples Alcohol, Suspension Most of the drugs ZERO ORDER FIRST ORDER InC = -kt + lnCo C = -Kot + Co LogC = -kt + LogCo / 2.3 -Ko = Y2-Y1 / X2-X1 -K = 2.3 (Log Y2-LogY1) / X2-X1 t1/2 = 0.5 Co / Ko t1/2 = 0.693 / K Co = C + Kot lnCo = lnC + Kt t = C- Co / Ko t = lnC- lnCo / K ZERO-ORDER KINETICS ZERO-ORDER KINETICS FIRST-ORDER KINETICS FIRST-ORDER KINETICS FIRST-ORDER KINETICS OUR LADY OF FATIMA UNIVERSITY College of Pharmacy Drug Stability Physical Pharmacy  Stability ◉ It can be defined as the ability of a particular formulation in a specific container or closure system to remain with in its physical, chemical, microbiological, therapeutic and toxicological specifications ◉ The period of stability of a preparation is the time from the date of manufacture of the formulation until its chemical or biological and is NLT 90% of the labelled potency TYPES OF STABILITY 4  Shelf Life ◉ Refers to the duration of time during which a drug preparation will remain physically, chemically, therapeutically, toxicology, and microbiology stable (possessing NLT 90% of the labeled potency) ◉ It also indicates the period when the formulation is expected to remain “fit for use” under ordinary conditions of handling and storage in the environment such as warehouse, home, hospital and pharmacy shelf  Expiration Date ◉ It is the direct application and interpretation of knowledge gained from stability testing ◉ It limits the period during which a preparation may be expected to have its labeled potency, provided the product has been stored as directed on the labeling ◉ The storage requirements must be observed throughout the distribution of the product, i.e. Beyond the time it leaves the manufacturer up to and including the time it is handled by the consumer  Important Parameters ◉ Drug Products ○ Loss of activity or potency of the active ingredient ○ Amount of degradation product ◉ Cosmetics ○ Retention of the physical qualities of freshly manufactured product ○ Instability that is gauged by its loss of elegance  Types of Stability Studies ◉ Short Term / Accelerated Stability Studies ○ This involves the use of Exaggerated conditions of temperature, light, moisture, pH and humidity to test the stability of drug formulations 3 mos acceptable data at 37-40C/75% RH for 2yr expiry ○ The purpose is to determine kinetic parameters, if possible and/or to predict the tentative expiration dating period  Significance of Accelerated Stability Studies ◉ To intensify the degradation loss with time ◉ To enable researchers to predict the shelf life of a product within a short period of time ◉ To determine the most stable formulation for a particular therapeutic actives (in preformulation studies)  Types of Stability Studies ◉ Long Term/Real Time Stability Studies ○ Conducted under the usual/normal conditions of the environment, transport and storage expected during product distribution 25C / 60% RH ± 5%. Duration of atleast 2yrs ○ It makes use of different “climatic zones” also called Global Assessment of Stability of Exposure Zone 1 = Temperate Zone 2 = Subtropical Zone 3 = Hot and Dry Zone 4 = Hot and Humid  Types of Stability Studies ◉ Stress Tests (done on API) ○ Involves the use of elevated temperatures in 10 degrees increments higher than those in ASS. ○ This test is performed until the total physical and chemical degradation of the product is reached ○ This stability testing has a duration of 6-12 months.  Stability Testing Schedules ◉ Over the 1st year of study = every 3 months ◉ Over the 2nd year of study = every 6 months ◉ Over the 3rd year and above of study = once a year TYPES OF STABILITY TESTING 13  Storage Temperatures Cold NMT 8°C (46°F) Refrigerator 2°-8°C (36-46°F) Freezer -20°C to -10°C (-4° to 14°F) Cool 8-15°C (46-59°F) Room Temperature Temperature prevailing in the area (Ambient) Controlled Temperature 15-30°C (59-86°F) Warm 30-40°C Excessive Heat Above 40°C (104°F)  Factors Affecting Stability of a Pharmaceutical Product ◉ Stability of Active Ingredients ◉ Potential Interactions between active and inactive ingredients ◉ Manufacturing process ◉ Container closure system ◉ Environmental conditions ◉ Storage ◉ Handling ◉ Length of time between handling manufacture and usage  Product Stability Evaluations ◉ Physical Stability is important to formulators for three primary reasons: ○ Appearance – a pharmaceutical product is expected to look fresh, elegant and professional no matter how long it stands on the shelf ○ Uniformity – the manufacturers must ensure that the patient will receive the proper amount of the active ingredient in each dose ○ Availability – the active ingredient must be available to the patient throughout the expected shelf life of the preparation  Product Stability Evaluations ◉ Chemical Stability – causes chemical deterioration incompatibilities which may be: ○ Physical – changes in the organoleptic properties of the drug ○ Chemical – changes in the chemical composition of the drug (such as oxidation, hydrolysis and reduction reaction, Racemization, Decarboxylation, Deterioration of H2O2 and Hypochlorites, and Formation of Precipitates) ○ Therapeutic – overdosage and underdosage of the active ingredients of the preparation  DRUG STABILITY ◉ The chemical breakdown of drugs: ◉ HYDROLYSIS ◉ Drug containing ester, amide, lactam, imide or carbamate groups are susceptible to hydrolysis ◉ H+ and OH- are the most common catalysts of hydrolytic degradation in solution. ◉ Esters usually undergo hydrolytic reactions that cause drug instability. ○ Esters can be converted into other esters (transesterification), the parent carboxylic acid (hydrolysis) or amides (see above). Transesterification : heat with alcohol and acid catalyst Hydrolysis : heat with aq. acid or base (e.g. aq. H2SO4 or aq. NaOH) (see hydrolysis of esters for more details) Amide preparation : heat with the amine, methyl or ethyl esters are the most reactive  OXIDATION ◉ Oxidation involves the removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical ◉ Oxidation is usually mediated through reaction with atmospheric oxygen under ambient conditions (auto- oxidation)  OXIDATION ◉ Example of drugs that are susceptible to oxidation include sterols, polyunsaturated fatty acids, phenothiazines, and drugs eg simvastatin and polyene antibiotics that contain conjugated double bonds ◉ Commonly used antioxidants include ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) , propyl gallate, sodium bisulfite, sodium sulfite, and the tocopherols.  PHOTOLYSIS ◉ Photolysis is the degradation of drug molecules by normal sunlight or room light  PHOTOCHEMICAL DECOMPOSITION ◉ Example of drugs that degrade when exposed to light include phenothiazines, hydrocortisone, prednisolone, riboflavin, ascorbic acid and folic acid ○ Coating tablets with polylmer film containing UV absorbers has been suggested as an additional method for protection from light  PHOTOCHEMICAL DECOMPOSITION ◉ Molecules may absorb the proper wavelength of light and acquire sufficient energy to undergo reaction. ◉ Usually, photolytic degradation occurs on exposure to light of wavelengths < 400 nm  ISOMERIZATION ◉ This is the process of conversion of a drug into its optical or geometric isomers, which are often of lower therapeutic activity ◉ Examples are epinephrine: racemization in acidic solution ◉ Others are tetracyclines, cephalosporins and vitamin A  POLYMERIZATION ◉ The process by which two or more identical drug molecules combine together to form a complex molecule ◉ Examples are amino-PCN eg ampicillin Na in aqueous solution, and also formaldehyde  ELECTROPHORESIS ◉ This involves the movement of charged particle through a liquid under the influence of an applied potential difference