Modern pharmacutics consolidation 5 unit.pptx

consolidation parameters, consolidation definition, consolidation parameters,
diffusion parameters,
dissolution parameters,
heckle plot, consolidation process, cold welding, fusion bonding, mechanical theory, inter molecular forces theory, liquid surface film theory, factors effecting consolidation, driving froces that facilitate diffusion, parameters related to diffusion in drug release, parameters in dissolution process, affect of agitation on dissolution, effect of dissolution fluid on dissolution, pH on dissolution fluid, viscosity effect on dissolution, effect of temperature on dissolution, pharmacokinetics parameters, C max, T max, AUC(area under curve), heckel plot, application and limitations of heckel plot, methods to compare dissolution profile, model independent method(F1 AND F2)difference factor, similarity factors, limits of difference factor and similarity factors, higuchi model(Diffusion matrix formulation), korsmeyer peppas model(the power law).

1. Study of C onsolidation Parameters Prepared by :PUTTAMREDDY KAVYASRI Under the guidance of Dr .V. Shanmugam 1 st year M.Pharm Department of pharmaceutics Mohan Babu School of pharmaceutical sciences(MBU)

2. Contents: D iffusion and Dissolution parameters Pharmacokinitic parameter s 1 2 3 4 5 Heckel plots f 1 and f 2 factors Consolidation Higuchi and peppas plots KORSMEYER-PEPPAS MODEL:(the power law)

3. Consolidation Involves an increase in the mechanical strength of a material resulting from particle- particle interactions. The action or process of making something stronger or more solid.

4. Consolidation process: 1. Cold welding: In this process when two surfaces of particles approach each other closely enough , their free surface energies results in strong attractive forces 2. Fusion bonding: It is either similar or dissimilar materials with similar grain structure are heated to the melting point (liquid state) of both. pressure pressure dyes dyes Before After

5. 3. Mechanical theory: As particles undergo deformation , the particle boundaries that the edges of the particle intermesh ,forming a mechanical bond.. 4. Inter molecular forces theory: Under pressure the molecules at the point of true contract between new, clean surface of the granules are close enough so that vander walls forces interact to consolidate the particle. 5. Liquid -surface film theory: Thin liquid film form bond between the particles which binds them together at the particle surface.the energy of compression produces melting of solution at the particle interface followed by subsequent solidification or crystallization thus resulting in the formation of bonded surfaces.

6. 1. 2. 3. 4. 5. Factors affecting consolidation Chemical nature of the materia l The extent of the available surface The presence of surface contaminants The inter surface distance The stress applied.

7. Diffusion parameters: Diffusion is the net movement of any matter moving from higher concentration to the region of lower concentration. Studying the diffusion parameters will help us to understand the PERMEATION AND DISTRIBUTION of drug molecules in living syste m According to frick’s diffusion law: Frick’s first law: The molecular flux due to diffusion is proportional to concentration gradient. J = -D negative sign indicates a decrease in concentration but flux is positive quantity dc = change in con. of material g/cm 3 D = diffusion of a penetrate , cm/sec2 Dx = change in the distance , cm. Fricks second law: It states the relation between the change in concentration gradient of the particles and time.

8. According to higuchi : Q =K Q :the amount of drug released in time t per unit area k :is higuchi constant k :time in hr. T

9. Driving force Example Concentration Passive diffusion Pressure Osmotic drug release Temperature Lyophilization Electric potential Electrophoresis Driving forces that facilitate diffusion : Parameters of diffusion process: 1.surface area A 2.Diffusion layer thickness, h 3.Diffusion coefficient, D 4.Drug solubility,Cs

10. Parameters in the diffusion process Surface area A Drug solubility,Cs Diffusion layer thickness, h Diffusion coefficient, D Sink condition Path length molecular collision viscosit y surface area and concentration Parameter related to diffusion in DRUG RELEASE

11. DISSOLUTION PARAMETER: The transfer of molecule or ions from a solid state into solution is know as dissolution. Dissolution and then diffusion is a pre-requisite for drug absorption. Importance of dissolution testing: It is predictor of in vivo dissolution performance of drug Rate limiting factor in determining the physiological availability of drug Quality control, tool for monitoring the uniformity and reproductability of production batches Research tool l

12. PARAMETER IN DISSOLUTION PROCESS Effect of agitation Effect of dissolution fluid . Influence of pH of dissolution fluid Effect of surface tension tension of the dissolution medium . 1 2 3 4

13. 5 6 7 8 9 Effect of viscosity of the dissolution medium Effect of presence of unreactive and reactive additives in the dissolution medium Volume of dissolution medium and sink condition Deaeration of the dissolution medium Effects of temperature of the medium

14. 1. Effect of agitation : The relationship between the intensity of agitation and the rate of dissolution varies considerably according to the type of agitation used,the shape and design of the stirrer and the physicochemical properties of the solid. For the basket method, 100 rpm usually is utilized while for the paddle procedure ,a 50-75 rpm is recommended. Dissolution test used high speed agitation may lack discriminative value and can yield misleading results.

15. Effect of dissolution fluid : Selection of proper medium for dissolution testing depends largely on the physicochemical properties of drug.

16. Influence of pH of dissolution fluid : In 1949, a committee assigned by the American drug and pharmaceutical manufacturers associations recommended the use of distilled water as the test medium for the disintegration test. It was observed that in many instances water and dilute acid gave closely comparable results. USP 5 include simulated gastric fluid as the medium for tablets containing ingredients which reacted more readily in acid solution than in water(e.g., calcium carbonate). The medium again was changed to water in USP 7. Changes in pH exert the greatest effect in terms of drug solubility. For week acids, the dissolution rate increases with increasing pH ,whereas, for week bases, the dissolution rate increases with decreasing pH.

17. Average pH of stomach in men is 1.9 and 2.5 in women. For tablets containing active ingredients, whose solubility are independent of pH, the dissolution rate does not vary significantly with changes in pH of the dissolution medium unless they contain certain excipients that are influenced by pH.

18. Effect of viscosity of the dissolution medium: If the interaction at the interfaces, occurs much faster than the rate of transport, such as in the case of diffusion controlled dissolution process, it would be expected that the dissolution rate decreases with an increase in viscosity. The rate of dissolution of zinc in HCL solution contacting sucrose was inversely proportional to the viscosity of solution. The stoles-Einstein equation expresses the diffusion coefficient as a function of viscosity, as can be seen from the following treatment. D = μ k T μ = mobility (velocity at a force of one dyne) k = Boltzmann constant (1.38 × 10 -16) dissolution rate is inversely proportional to viscosity

19. Effect of surface tension of the dissolution medium: Larger values of the surface tension increase the surface area exposed to the liquid, leading to higher dissolution rates and more dissolved soluble gas in the surrounding liquid. Addition of surfactant below the critical micelle concentration(CMC) can increase significantly the dissolution rate because of better penetration of the solvent into the tablet resulting in greater availability if drug surface.

20. Effect of presence of unreactive and reactive additives in the dissolution medium When neutral ionic compounds, such as sodium chloride and sodium sulfate, or non ionic organic compounds,such as dextrose, were added to the dissolution medium the dissolution of benzoic acid was dependent linearly upon its solubility in the particular solvent. When certain buffers or bases were added to the aqueous solvent ,an increase in the dissolution rate was observed.

21. Volume of dissolution medium and sink condition The proper volume of the dissolution medium depends mainly on the solubility of the drug in the selector fluid. The drug is poorly soluble in water ,a relatively large amount of fluid should be used if complete dissolution is to be expected. In order to maintain the effect of the concentration gradient and maintain sink conditions, the concentration of the drug should not exceed 10 -15% of its maximum solubility in the dissolution medium selected.

22. Deaeration of the dissolution medium Presence of dissolved air or other gases in the dissolution medium may influence the dissolution rate of certain formulations and lead to variable and unreliable results. example, the dissolved air in distilled water could significantly lower its pH and consequently affect the dissolution rate of that are sensitive to pH changes, e.g., week acids. aeration also helps remove dissolved metals through oxidation

23. Effects of temperature of the medium Drug solubility is temperature dependent , therefore careful temperature control during the dissolution process is extremely important. Generally a temperature of 37 c +-0.5 is maintained during dissolution determination of oral dosage forms and suppositories. For topical preparations as low as 30 c and 25 c have been used.

24. Pharmacokinetics parameters : Pharmacokinetics is defined as the kinetics of drug absorption, distribution, metabolism, and excretion and their relationship with pharmacologic, therapeutic or toxicological response in humans and animals. The important pharmacokinetic parameters: 1. Peak plasma concentration (C max). 2. Time of plasma concentration (t max). 3. Area under the curve (AUC).

25. 1.Peak plasma concentration (C max): The point of maximum concentration of a drug in plasma is called as peak and the concentration of drug at peak is known as peak plasma concentration. It is also called as peak height concentration and maximum drug concentration. C max is expressed in mcg/ml.

26. 2. Time of peak concentration (T max) : The time for drug to reach peak concentration in plasma (after extra vascular administration) is called the time of peak concentration. It expressed in hours Onset time and onset of action is dependent upon t max. The parameter is of particular importance in assessing the efficacy of drugs used to treat acute conditions lie pain and insomnia.

27. 3. Area under the curve (AUC): It represents the total integrated area under the plasma level-time profile and expresses the total amount of drug that comes into the systemic circulation after its administration. AUC is expressed in mcg/ml X HRS. It is important for the drugs that are administered repetitively for the treatment of chronic conditions like asthma or epilepsy.

28. Heckel plot: It is the graphical representation of the relationship between the densification of powder bed and applied pressure. The equation describes the relationship between the process relating porosity and the hydrostatic pressure. Follow first order kinetics. As porosity increases compression force also increases. Log( 1/1-D)=Ky . P+A where, Ky = material dependent constant but inversely proportion; to its yield strength(S) D = relative density of the compact A= it a constant suggested to represent particle rearrangement and the reciprocal of K is used to calculate apparent mean yield pressure(Py).

29. BASED ON HECKEL EQUATION: 3 types of powders: 1.Type-A, 2.Type-B, 3.Type-C. FOR TYPE - A MATERIAL: A linear relationship is observed , the plots remaining parallel as the applied pressure is increased indicating deformation apparently only by plastic deformation. Soft materials undergo plastic deformation readily and retain different degree of porosity, depending upon the initial packing of die. thus, inturn influenced by the size distribution,shape etc., of the original particle s. e.g: sodium chloride

30. FOR TYPE -B MATERIAL: There is an initial curved region followed by a straight line. This indicates that the particles are fragmenting at the early stages of the compression process. Harder materials with higher yield pressure values usually undergo compression by fragmentation first, to provide a denser packing. e.g:Lactose;sucrose. FOR TYPE-C MATERIALS: There is an initial step linear region which become superimposed and flatten out as applied pressure is increased. This behaviour to the absence of a rearrangement stage and densification is due to plastic deformation and asperity melting.

31. Type-A plots,exhibits higher slope(Ky) than type-b,because type-a have lower yields stress than type-A Type-B plots,exhibits lower slope(Ky)because brittle,hard materials are difficult to compress.

32. Limitations: Heckel plot is influenced by: 1. Degree of lubrication. 2. Size of the die. 3residual porosity in particular formulations provide good mechanical strength,rapid water intake and hence good disintegration characteristics.. Application: 1. Used for check lubricant efficacy. 2. For interpretation of consolidation mechanism 3.it identifies the predominant form of deformation for a given sample 4.heckel plot represent in two regions: 1. initial repacking state. 2. Subsequent deformation proces s..

33. METHODS TO COMPARE DISSOLUTION PROFILE Graphical method statistical analysis Model Dependent method Model independent method t Test ANOVA First order Hixson-crowell Higuchi model Korsemeyar and peppas model Baker lansdale model Zero order Pair wise procedure(f1 and f2)

34. Model independent method: MOORE and FLANNER propose this mathematical approach to compare dissolution profile using 2 factors. PAIRED WISE APPOARCH : Difference factor(F1) Similarity factor(F2)

35. DIFFERENCE FACTOR(f1) SIMILARITY FACTOR(f2) The difference factor (f1) defined by FDA calculates the %difference between 2 curves at each time point and is a measurement of the relative error between 2 cures. It is defined by logarithmic reciprocal square root transformation of sum of squared error and is a measurement of the similarity in the percentage dissolution between the 2 curves.

36. where; n = no.of time points. Rt = %dissolution at time ‘t’ of reference product (per change) Ty =%dissolved at time ‘t’ of test product(post changes) . DIFFERENCE FACTR SIMILARITY FACTOR INFERENCE 100 Dissolution profile are similar ≤ 15 ≥ 50 Similarity or equivalence of two profiles Limits for similarity and difference factors:

37. The evaluation of similarity between dissolution profile is based on following conditions: Minimum of three dissolution time points are measured. Number of drug products tested for dissolution is 12 for both test and reference. Not more than one mean value of >85% dissolved for each product. Standard deviation of mean of any product should not be more than 10% from 2nd to last dissolution time point.

38. Advantage: They are easy to compute. They provide a single number to describe the comparison of dissolution profile data. They are easy to produce. Disadvantage: The values of f1 and f2 are sensitive to the number of dissolution time point used. If the test and reference formulation are interchanged ,f2 is unchanged but f1 is not, yet difference between two mean profile remains same. The basis of criteria for the difference or similarity between dissolution profile in unclear.

39. Applications: FOR F1: F1 is specially used to compare two dissolution profiles being necessary to consider one of them as reference and std. product. It can measure the percent of error between two curves overall time points. FOR F2: This method is more appropriate when more than 3 or 4 dissolution time points are available. The f2 may became invariant with respect to location change and consequence of failure to take into account the shape of cure and unequal spacing between sampling time points leads to errors. Nevertheless with the slight modification in the statistical analysis,similarity factor would definitely serves as an efficient tool for reliable comparison of dissolution profiles.

40. HIGUCHI MODEL: (Diffusion matrix formulation) Higuchi proposed is model to describe drug release from matrix system. It is developed to study the water soluble and low soluble drugs incorporated in semisolid and solid matric s. It is based on the hypothesis that; 1. Initial drug concentration in the matrix is much higher than drug solubility. 2. Drug diffusion takes place in only one direction(edge effect must be negligible.) 3. Drug particles are much smaller than system thickness. 4. Matrix swelling and dissolution are negligible. 5. Drug diffusivity is constant. 6. Prefect sink conditions are always attained in the release environment.

41. Higuchi model is given by the equation: Q =K H . √T (or) Q =A√D(2C-C)CS. T Where; Q=amount of drug released in time ‘t’per unit area. K h =hiuchi constant C=initial drug concentration T=time(hrs) C S =drug solubility in matrix media D=diffusivity of drug molecules in solvent. APPLICATIONS: Modified release pharmaceutical dosage forms , trandermal systems and matrix tablets with water soluble drugs.

42. What is the significance HIGUCHI’S EQUATION/MODEL....... . It describes the drug release as a diffusion process based on the fick’s law which is square root time dependent. water soluble drug # Pentoxyphylline Poorly water soluble drug #Morphine Semi solids #Diclofenac gel. Solids. Some trans dermal patches

43. KORSMEYER-PEPPAS MODEL:(the power law) A simple relationship which described drug release from a polymeric system equation was derived by korsmeyer F = Mt / M = Kt n Where, Mt / M =drug released at time ‘t’ k =release rate constant n =release exponent or diffusion F =fraction of drug released at time ‘t’ Mt =amount of drug released at time’ m = total amount of drug in dosage form Graphical representation log %CDR vs time taken

44. significance of KORSMEYER PEPPAS EQUATION..... 1.Release behaviour of drug from hydrophilic matrix. 2.It is applicable to linearization of release data from micro capsules and micro spheres. This equation can be used to analyze the first 60% of a release curve, regardless of geometric shape. Fickian diffusion release and case -2 relaxation release, are the limits of this phenomenon. Hence modification was need for above started condition. Erosion controlled release rate Diffusion release rate Anomalous diffusion or Non fickian diffusion Anomalous or non -fickian diffusion means rates of solvent penetration and drug release in the same range .It refers to combination of both diffusion and erosion controlled rate release.

45. n is estimated from linear registration of log (Mt/m)versus log t n INDICATION Less than 0.45 Quasi fickian 0.45 fickian diffusion 0.45 < n < 0.89 anomalous diffusion or non fickian diffusion 0.89-1 zero order case-2 relaxation or non fickian case 2 <1 Non fickian super case 2

46. REFERENCES: 1. Theory and Practice of Industrial Pharmacy By Lachmann and Lieberman 2. Pharmaceutical dosage forms: Tablets Vol. 1-3 by Leon Lachmann. 3. Pharmaceutical Dosage forms: Disperse systems, Vol, 1-2; By Leon Lachmann. 4. Pharmaceutical Dosage forms: Parenteral medications Vol. 1-2; By Leon Lachmann. 5. Modern Pharmaceutics; By Gil l bert and S. Banker. 6.https://www.slideshare.net/sagarsavale1/drug-release-kinetics 7.Biopharmaceutics and pharmacokinetics by D.M. Bhramankar and Sunil b.Jaiswal

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