COMPACTION PROFILES,SOLUBILITY ENHANCEMENT TECHNIQUES,STUDY.pptx
- 1. COMPACTION PROFILES,SOLUBILITY ENHANCEMENT TECHNIQUES,STUDY OF CONSOLIDATION PARAMETERS (DIFFUSION PARAMETERS,DISSOLUTION PARAMETERS AND PHARMACOKINETICS PARAMETERS) PRESENTED BY NIVEDITHA G 1st sem Mpharm (Department Of Pharmaceutics) NARGUND COLLEGE OF PHARMACY
- 2. COMPACTION PROFILES • Many attempts have been made to minimize the amount of applied force transmitted radially to the die walls. All such investigations lead to characteristic hysteresis curves called as compaction profiles. Radial pressure is developed due to the attempt of material to expand horizontally. The plot of radial pressure against axial pressure leads to hysteresis curve called as compaction profile. • When the elastic limit of the material is high, elastic deformation may make the major contribution, and on removal of the applied load, the extent of the elastic relaxation depends on the value of the material’s modules of elasticity (young’s modulus).
- 3. • Lower the modulus higher will be the elastic relaxation. Then there will be the danger of structural failure. • Higher the modulus value results in low decompression hence lesser risk of structural failure
- 4. •Examples of compaction profiles. •Dotted line O to A represents a highly variable response due to repacking. • At A elastic deformation becomes dominant and continues until the elastic limit B is reached. • From B to the point of maximum compression C, deformation is predominantly plastic, or brittle fracture is taking place. • The decompression process C to D is accompanied by elastic recovery, and if a second yield point D is reached. • Plastic deformation or brittle fracture takes place from D to E. • And the decompression line B to C represents the behaviour of a largely elastic material
- 5. SOLUBILITY ENHANCEMENT TECHNIQUES • The term ‘solubility’ is defined as maximum amount of solute that can be dissolved in a given amount of solvent. It can also be defined quantitatively as well as qualitatively. • Quantitatively it is defined as the concentration of the solute in a saturated solution at a certain temperature. • In qualitative terms, solubility may be defined as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion. • The solubility of a drug is represented through various concentration expression such as parts, percentage, molarity, molality, volume fraction, mole fraction.
- 6. Need for solubility enhancement • There are variety of new drugs & their derivatives are available. But less than 40% of lipophilic drugs candidates fail to reach market due to poor bioavailability, even though these drugs might exhibit potential pharmaco-dynamic activities. • The lipophilic drug that reaches market requires a high dose to attain proper pharmacological action. • The basic aim of the further formulation & development is to make that drug available at proper site of action within optimum dose.
- 7. Importance of enhancement • Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. • Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic development. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. The techniques are chosen on the basis of certain aspects such as properties of drug under consideration, nature of excipients to be selected, and nature of intended dosage form. • These poorly water-soluble drugs having slow drug absorption leads to inadequate and variable bioavailability and gastrointestinal mucosal toxicity.
- 10. Particle Size Reduction • The bioavailability intrinsically related to drug particle size. By reducing particle size, increased surface area improves the dissolution properties. • Nowadays Particle size reduction can be achieved by micronization and nanosuspension. The techniques involved in particle size reduction are: 1. Micronization 2. Nanosuspension
- 11. Micronization • In micronization the solubility of drug is often intrinsically related to drug particle size. By reducing the particle size, the increased surface area improves the dissolution properties of the drug. • Micronization increases the dissolution rate of drugs through increased surface area, it does not increase equilibrium solubility. • Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills etc.
- 12. Micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug. • These processes were applied to griseofulvin, progesterone, spironolactone and fenofibrate. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy. 2. Nanosuspension • Nanosuspension is another technique which is sub-micron colloidal dispersion of pure particles of drug, which are stabilized by surfactants.
- 13. • The advantages offered by nanosuspension is increased dissolution rate is due to larger surface area exposed, while absence of Ostwald ripening is due to the uniform and narrow particle size range obtained, which eliminates the concentration gradient factor. • Nanosuspensions are produced by homogenization and wet milling process. • The nanosuspension approach has been employed for drugs including Tarazepide, Atovaquone, Amphotericin B, Paclitaxel and Bupravaquon. Modification Of Crystal Habit (or)Crystal Engineering • The controlled crystallization of drugs to produce high purity powders with well- defined particle size distribution, crystal habit, crystal form (crystalline or amorphous), surface nature, and surface energy.
- 14. • By manipulating the crystallization conditions (use of different solvents or change in the stirring or adding other components to crystallizing drug solution) a variety of crystal habit is generated. • Polymorphs • Amorphous • Co crystallization
- 15. Polymorphs • It is possible to prepare crystals with different packing arrangement; such crystals are called polymorphs. As a result, polymorphs for the same drug may differ in their physicochemical properties such as solubility, dissolution rate, melting point, and stability. • Most drugs exhibit structural polymorphism and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf-life under a variety of real-world storage conditions.
- 16. Amorphous • Amorphous materials exhibit distinct physicochemical properties compared to their respective crystalline counterparts. • One of these properties, the increased solubility of amorphous materials, is exploited in the pharmaceutical industry as a way of increasing bioavailability of poorly water-soluble drugs. Co crystallization • Pharmaceutical cocrystals open a new avenue to address the problems of poorly soluble drugs. They contain two or more distinct molecules arranged to create a new crystal form whose properties are often superior to those of each of the separate entities. • The pharmaceutical cocrystals are formed between a molecular or ionic drug and a cocrystal former that is a solid under ambient conditions.
- 17. • These are prepared by slow evaporation from a drug solution containing stoichiometric amounts of the components (cocrystal formers); however, sublimation, growth from the melt, or grinding of two or more solid cocrystal formers in a ball mill are also suitable methodologies SUPERCRITICAL FLUID RECRYSTALLIZATION(SCF) • Those fluids are referred to as supercritical fluids which are having temperature and pressure greater than its critical temperature and critical pressure so as they are acquire properties of both gas and liquid e.g.:-carbon dioxide. • As the drug gets solubilized within SCF they can be recrystallized with reduced particle size of drug
- 18. SONOCRYSTALLISATION • The novel approach for particle size reduction on the basis of crystallization by using ultrasound is Sonocrystallisation. • Sonocrystallisation utilizes ultrasound power characterized by a frequency range of 20–100 kHz for inducing crystallization. • It’s not only enhances the nucleation rate but also an effective means of size reduction and controlling size distribution of the active pharmaceutical ingredients. • Most applications use ultrasound in the range 20 kHz-5 MHz.
- 19. Drug Dispersion Carriers Eutectic mixtures • Its potential as a system to improve the solubility and dissolution of poorly water-soluble drugs. • When the eutectic mixture is exposed to water the soluble carrier dissolves leaving the drug in a microcrystalline state which solubilize rapidly. Solid dispersions • The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. • In this technique, a poorly soluble drug is dispersed in a highly soluble solid hydrophilic matrix, which enhances the dissolution of the drug
- 20. Solid dispersions These are prepared by using several methods, such as the fusion (melt) method and the solvent method • The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone (Povidone, PVP), polyethylene glycols (PEGs), PlasdoneS630. • Surfactants like Tween-80, docusate sodium, and sodium lauryl sulphate (SLS) also find a place in the formulation of solid dispersion. • A solid dispersion of griseofulvin and polyethylene glycol 8000 (Gris- PEG®) is commercially available
- 21. 1. Solid solutions • Solid solutions are generally made by the “melt method” or the “solution method” • In the solution method, API and excipients are co-dissolved in a solvent, which is then removed to form the dosage form. • Two components crystallize together in a homogeneous one phase system, because of reduction in particle size to the molecular level solid solution shows greater aqueous solubility. • E.g., Griseofulvin from such solid solution dissolves 6-7 times faster than pure form.
- 22. 2. Cryogenic techniques • It is developed to enhance the dissolution rate of drugs by creating nanostructured amorphous drug particles with high degree of porosity at very low-temperature conditions. • Cryogenic inventions can be defined by the type of injection device (capillary, rotary, pneumatic, and ultrasonic nozzle), location of nozzle (above or under the liquid level), and the composition of cryogenic liquid (hydrofluoroalkanes, N2, Ar, O2, and organic solvents).
- 23. Chemical Modification • Change of pH • Use of buffer • Derivatization • Complexation • Salt formation
- 24. pH Adjustment • Poorly water-soluble drugs with parts of the molecule that can be protonated (base) or deprotonated (acid) may potentially be dissolved in water by applying a pH change. pH adjustment can in principle be used for both oral and parenteral administration. • In the stomach the pH is around 1 to 2 and in the duodenum the pH is between 5-7.5, so upon oral administration the degree of solubility is also likely be influenced as the drug passes through the intestines. Ionizable compounds that are stable and soluble after pH adjustment are best suited. • pH adjustment is also frequently combined with co-solvents to further increase the solubility of the poorly soluble drug.
- 25. Use of buffer Buffer maintains the pH of the solution overtime and it reduces or eliminate the potential for precipitation upon dilution. On dilution pH alteration occurs that decrease solubility. • Change of pH by 1 fold increase solubility by 10fold if it changes by one pH unit, that decrease ionisation of the drug and solubility decreases by 10 fold Derivatization • It is a technique used in chemistry which transforms a chemical compound into a product of similar chemical structure, called derivative. • Derivatives have different solubility as that of adduct. It is used for qualification of adduct formation of esters and amides via acyl chlorides.
- 26. Complexation • Complexation of drugs with cyclodextrins has been used to enhance aqueous solubility and drug stability. • Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8 dextrose molecules (α, β, γcyclodextrin) bound in a 1,4-configuration to form rings of various diameters. • The ring has a hydrophilic exterior and lipophilic core in which appropriately sized organic molecules can form noncovalent inclusion complexes resulting in increased aqueous solubility and chemical stability. • Complexation relies on relatively weak forces such as London forces, hydrogen bonding and hydrophobic interactions
- 27. Technique Of Complexation Physical Mixture. 1. Kneading Method • Active drug with suitable polymer in different ratios is added to the mortar and triturated with small quantity of ethanol to prepare a slurry • Slowly the drug is incorporated into the slurry with constant trituration. The prepared slurry is then air dried at 250 for 24hrs. • The resultant product is pulverized and passed through sieve no. 80 and stored in desiccator over fused calcium chloride
- 28. 2.Co-precipitate Method • Active drug is dissolved in ethanol at room temperature and suitable polymer is dissolved in distilled water. • Different molar ratios of active drug and suitable polymers are mixed respectively • The mixture is stirred at room temperature for one hour and the solvent is evaporated. The resultant mass is pulverized and passed through sieve no. 80 and stored in a desiccator
- 29. 3.SPRAY DRYING • The solvent evaporation of drug and polymer solution in different ratio is carried out by using spray dryer. • The solutions are prepared by dissolving drug in methanol and polymer in distilled water and mix both solutions, which produces a clear solution. • The solvent evaporated by using evaporator. • The spray dried mixture of drug with polymer is obtained in 20–30 min. 4. INCLUSION COMPLEX FORMATION • Inclusion complexes are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule (known as guest) into the cavity of another molecule or group of molecules (known as host). EX b- cyclodextrin
- 30. • The cavity of host must be large enough to accommodate the guest and small enough to eliminate water, so that the total contact between the water and the nonpolar regions of the host and the guest is reduced TECHNIQUES OF INCLUSION COMPLEX METHOD 1.Lyophilization/Freeze-Drying Technique: ➢ In order to get a porous, amorphous powder with high degree of interaction between drug and CD. ➢ In this technique, the solvent system from the solution is eliminated ➢ through a primary freezing and subsequent drying of the solution containing both drug and CD at reduced pressure. ➢ Thermolabile substances can be successfully made into complex form by this method
- 31. 2.Microwave Irradiation Method: ➢ This technique involves the microwave irradiation reaction between drug and complexing agent using a microwave oven. SALT FORMATION • Dissolution rate of particular salt is usually different from that of parent compound. • Sodium and potassium salt of week acid dissolve more rapidly than that of pure salt. ❑ Limitation of salt formation- ➢ Epigastric distress due to high alkalinity, ➢ Reactivity with atmospheric water and carbon dioxide leads to precipitation, ➢ Patient compliance and commercialization.
- 32. Miscellaneous Surfactant • Surfactants are the agents which reduces surface tension and enhance the dissolution of lipophilic drugs in aqueous medium. • The surfactants are also used to stabilize drug suspensions. • When the concentration of surfactants more than their critical micelle concentration (CMC, which is in the range of 0.05–0.10% for most surfactants), micelle formation occurs which entrap the drugs within the micelles. This is known as micellization and generally results in enhanced solubility of poorly soluble drugs. Microemulsions • A microemulsion is an optically clear pre-concentrate containing a mixture of oil, hydrophilic surfactant and hydrophilic solvent which dissolves a poorly water- soluble drug.
- 33. • Microemulsions have been employed to increase the solubility of many drugs that are practically insoluble in water, along with incorporation of proteins for oral, parenteral, as well as percutaneous / transdermal use SOLUBILIZERS • The solubility of poorly soluble drug can also be improved by various solubilizing materials. • PEG 400 is improving the solubility of hydrochlorthiazide 85. • Modified gum karaya a recently developed excipient was evaluated as carrier for dissolution enhancement of poorly soluble drug nimodipine.
- 34. COSOLVENCY • The solubility of poorly soluble drugs in water can be increased by mixing it with some water miscible solvent in which the drug is readily soluble. This process is known as co solvency and the solvent used in combination are known as cosolvent. • The cosolvents are having hydrogen acceptor or donor groups with a small hydrocarbon region. • The hydrophobic hydrocarbon region usually interferes with the hydrogen bonding network of water which consequently reduces the intermolecular attraction of water while the hydrophilic hydrogen bonds ensures water solubility.
- 35. HYDROTROPY ➢ Hydrotropy is a solubilization phenomenon whereby addition of large amount of a second solute results in an increase in the aqueous solubility of existing solute. ➢ Concentrated aqueous hydrotropic solutions of sodium benzoate, sodium salicylate, urea, nicotinamide, sodium citrate, and sodium acetate have been observed to enhance the aqueous solubilities of many poorly water-soluble drug.
- 36. Applications of solubility • Solubility is representing a fundamental concept in fields of research such as chemistry, physics, food science, pharmaceutical, and biological sciences. • The solubility of a substance becomes especially important in the pharmaceutical field because it often represents a major factor that controls the bioavailability of a drug substance. • Solubility is commonly used to describe the substance, to indicate a substance's polarity, to help to distinguish it from other substances, and as a guide to applications of the substance. • Solubility of a substance is useful when separating mixtures. • Moreover, solubility and solubility-related properties can also provide important information regarding the structure of drug substances, and in their range of possible intermolecular interactions. • It is used for enhancing solubility of class 2 drugs of BCS
- 37. Diffusion, Dissolution and Pharmacokinetic parameters Diffusion: Diffusion is the movement of a substance from an area of high concentration to an area of low concentration. • Diffusion happens in liquids and gases because their particles move randomly from place to place. • The material that undergoes diffusion is known as diffusant or permeant or penetrant.
- 38. Example: 1. When shaking salt into water, the salt dissolves and the ions move until they are evenly distributed. 2. After placing a drop of food coloring onto a square of gelatin, the color will spread to a lighter color throughout the block. Factors affecting diffusion. 1. Temperature : Higher temperature diffuse faster 2. Surface area : Larger surface area greater in diffusion 3. Concentration : Higher the concentration gradient greater the diffusion 4. Particle size: Smaller the particles greater the diffusion. Diffusion parameters This is given by Higuchi. 𝑄 = 𝐾 𝑻 Where, Q is the amount of drug released in time‘t’ per unit area
- 39. • K is higuchi constant, T is time in hr. • Plot: The data obtained is to be plotted as cumulative percentage drug release versus Square root of time. • Application: modified release pharmaceutical dosage forms, transdermal systems and matrix tablets with water soluble drugs. Dissolution : Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Example; Tablet when comes in contact with surrounding liquid tablet gets converted in liquid phase
- 40. Dissolution parameters: 1. Effect of agitation. 2. Influence of pH of dissolution fluid. 3. Effect of surface tension of the dissolution medium. 4. Effect of viscosity of the dissolution medium 5. Effect of the presence of unreactive and reactive additives in the dissolution medium. 6. Volume of dissolution medium and sink conditions. 7. Deaeration of the dissolution medium. 8. Effect of temperature of the dissolution medium. 9. Volume of dissolution medium and sink conditions. 10. Deaeration of the dissolution medium. 11. Effect of temperature of the dissolution medium
- 41. Effect of agitation: The relationship between the intensity of agitation and the rate of dissolution varies considerably according to the type of agitation used, degree of laminar and turbulent flow in the system, the shape and design of the stirrer and the physicochemical properties of the solid. ❑ Dissolution test using high speed agitation may lack discriminative value and can yield misleading results. ❑ Accordingly, the compendial methods in general, are conducted under relatively low agitation. ❑ For the basket method, 50 or 100 rpm usually is utilized, while for the paddle procedure, a 50 rpm is recommended. ❑ In case of the non official continuous flow, column type methods, a flow rate of 10 – 100 ml/min commonly is employed
- 42. Influence of pH of dissolution fluid • it was observed that USP XV included simulated gastric fluid as the test 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 the USP XVIII. ❑ Changes in pH exert the greatest effect in terms of drug solubility. ❑ For weak acids, the dissolution rate increases with increasing pH, whereas, for weak bases, the dissolution rate increases with decreasing pH. ❑ Therefore for acetylsalicylic acid (pKa=3.5) tablets and capsules, the dissolution rate would be expected to increase if the pH of the dissolution medium was higher than 3.
- 43. • ❑ For tablets containing active ingredients, whose solubilities 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. • ❑ For example, Tablets that are formulated with carbon dioxide producing compounds, such as sodium bicarbonate, magnesium carbonate or calcium carbonate, tend to have slightly faster dissolution rate in acid medium than in water because rapid disintegration increases the effective surface area.
- 44. Effect of surface tension of the dissolution medium • According to the diffusion film theory, dissolution of the drug is governed by the interplay between two processes, the release of the drug from the solid surface and its transfer throughout the bulk of the dissolution medium. • If the drug is hydrophobic the dissolution rate is influenced primarily by the release processes, whereas, for hydrophilic drugs the transfer process is more likely to be the rate limiting step. • Incorporation of surface active agents in the dissolution medium, is expected to enhance the dissolution rate of a poorly soluble drug in solid dosage forms by reducing the interfacial tension and micelle formation. • 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.
- 45. 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 processes, it would be expected that the dissolution rate decreases with an increase in viscosity. ▪ The rate of dissolution of zinc in HCl solution containing sucrose was inversely proportional to the viscosity of solution. ▪ The stokes- Einstein equation expresses the diffusion ▪ coefficient as a function of viscosity, as can be seen from the following treatment 𝐷 = μ𝑘𝑇 ▪ D= diffusion coefficient ▪ μ = mobility (velocity at a force of one dyne) ▪ k = Boltzmann constant (1.38 × 10− 16 ) ▪ T=temperature
- 46. Effect of the 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
- 47. Volume of dissolution medium and sink conditions The proper volume of the dissolution medium depends mainly on the solubility of the drug in the selected fluid. • If 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
- 48. 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 drugs that are sensitive to pH changes, e.g., weak acids. • Another serious effect is the tendency of the dissolved air to be released from the medium in the form of tiny air bubbles that circulate at random and invariably affect the of the hydrodynamic flow pattern generated by the stirring mechanism. • The gathering of air bubbles on the solid surface could also lead to a reduction in the specific gravity to the point where the tablet, or its disintegrating powder bed, float to the top of the basket in the liquid medium with a minimum chance of being wetted efficiently
- 49. Effect of temperature of the dissolution medium: Drug solubility is dependent on temperature, therefore careful temperature control during the dissolution process is extremely important. ➢ Generally a temperature of 37°±0.5 is maintained during dissolution determination of oral dosage forms and suppositories. ➢ For topical preparations as low as 30° and 25°have been used. ➢ The effect of temperature variations of the dissolution medium depends on the temperature/ solubility curves of the drug and the excipients in the formulation. ➢ Carstetensen pointed out that for a diffusion coefficient D is dependent upon the temperature.
- 50. • Carstensen gave an equation 𝑈𝑘𝑇 Where, U = mobility ( defined as the velocity when exposed to a force of one dyne) k = Boltzmann constant T = absolute temperature Hixson-Crowells cube root law: Hixson and Crowell described this ➢ W0 1/3 − Wt 1 /3 = Kt Where, W0 is the initial amount of drug Wt is the remaining amount of drug at time t .
- 51. Plot: Data is to be plotted as cube root of drug percentage remaining in matrix versus time. ➢ Application: • This expression applies to pharmaceutical dosage form such as tablets, where the dissolution occurs in planes that are parallel to the drug surface if the tablet dimensions diminish proportionally in such a manner that the initial geometrical form keeps constant all the time.
- 52. Pharmacokinetic parameters • Pharmacokinetics is defined as the kinetics of drug absorption, distribution, metabolism, and excretion and their relationship with pharmacologic, therapeutic or toxicologic response in humans and animals.
- 53. • Three important pharmacokinetic parameters 1.Peak plasma concentration (Cmax) 2. Time of peak concentration (tmax) 3. Area under the curve (AUC) Peak plasma concentration (Cmax) 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. ❖ Cmax is expressed in µg/ml
- 54. Time of peak concentration (tmax) • The time for drug to reach peak concentration in plasma ( after extravascular administration) is called the time of peak concentration. • ✓ It is expressed in hours. Onset time and onset of action is dependent upon tmax. • ✓ The parameter is of particular importance in assessing the efficacy of drugs used to treat acute conditions like pain and insomnia.
- 55. 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 µg/ml x Hours. ❖ It is important for the dugs that are administered repetitively for the treatment of chronic conditions like asthma or epilepsy
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