INTERNATIONAL JOURNAL OF RESEARCH AND REVIEWS IN PHARMACY

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Dharmendra singet al, IJRRPAS, 2(2).305-341,

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International Journal of Research and Reviews in Pharmacy and Applied science www.ijrrpas.com

SOLUBILITY & DISSOLUTION

Corresponding Author Dharmendra singh sisodiya Ronak Patel Avinash nigam B.N.College of Pharmacy

ABSTRACT Solubility is of fundamental importance in a large number of scientific disciplines

[email protected]

and practical applications, ranging from ore processing, to the use of medicines, and

Mobile: 09509261411

the transport of pollutants. Dissolution tool testing has become an integral part of quality control, although official methods are used, there exists no standard methods for evaluation of a solid dosage form. The method and standards, which correlate well with the in-vivo data, should be utilized. The knowledge not only acts as tool for q.c.It

also

assists

in

preformulation

studies and

in

understanding

the

biopharmaceutical role.

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SOLUBILITY: INTRODUCTION Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on temperature and pressure. The extent of the solubility of a substance in a specific solvent is measured as the saturation concentration where adding more solute does not increase the concentration of the solution.Most often, the solvent is a liquid, which can be a pure substance or a mixture.[1] One may also speak of solid solution, but rarely of solution in a gas (see vapor-liquid equilibrium instead). The extent of solubility ranges widely, from infinitely soluble (fully miscible[2] ) such as ethanol in water, to poorly soluble, such as silver chloride in water. The term insoluble is often applied to poorly or very poorly soluble compounds.Under certain conditions, the equilibrium solubility can be exceeded to give a so-called supersaturated solution, which is metastable.3 Solubility is not to be confused with the ability to dissolve or liquefy a substance, because the solution might occur not only because of dissolution but also because of a chemical reaction. For example, zinc is insoluble in hydrochloric acid, but does dissolve in it by chemical reaction into zinc chloride and hydrogen, where zinc chloride is then soluble in hydrochloric acid. Solubility does not also depend on particle size or other kinetic factors; given enough time, even large particles will eventually dissolve.solubility is the analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent. Solubility may be stated in units of concentration, molality, mole fraction, mole ratio, and other units.4Solubility occurs under dynamic equilibrium, which means that solubility results from the simultaneous and opposing processes of dissolution and phase joining (e.g., precipitation of solids). The solubility equilibrium occurs when the two processes proceed at a constant rate. The term solubility is also used in some fields where the solute is altered by solvolysis. For example, many metals and their oxides are said to be "soluble in hydrochloric acid," whereas the aqueous acid degrades the solid to irreversibly give soluble products. It is also true that most ionic solids are degraded by polar solvents, but such processes are reversible. In those cases where the solute is not recovered upon evaporation of the solvent, the process is referred to as solvolysis. The thermodynamic concept of solubility does not apply straightforwardly to solvolysis. When a solute dissolves, it may form several species in the solution. For example, an aqueous suspension of ferrous hydroxide, Fe(OH)2, will contain the series [Fe(H2O)6 − 306 Available on www.ijrrpas.com

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as well as other oligomeric species. Furthermore, the solubility of ferrous hydroxide and the composition of its soluble

components depends on pH. In general, solubility in the solvent phase can be given only for a specific solute that is thermodynamically stable, and the value of the solubility will include all the species in the solution (in the example above, all the iron-containing complexes).

Factors affecting solubility: Solubility is defined for specific phases. For example, the solubility of aragonite and calcite in water are expected to differ, even though they are both polymorphs of calcium carbonate and have the same chemical formula.The solubility of one substance in another is determined by the balance of intermolecular forces between the solvent and solute, and the entropy change that accompanies the solvation. Factors such as temperature and pressure will alter this balance, thus changing the solubility. Solubility may also strongly depend on the presence of other species dissolved in the solvent, for example, complex-forming anions (ligands) in liquids. Solubility will also depend on the excess or deficiency of a common ion in the solution, a phenomenon known as the common-ion effect. To a lesser extent, solubility will depend on the ionic strength of solutions. The last two effects can be quantified using the equation for solubility equilibrium. For a solid that dissolves in a redox reaction, solubility is expected to depend on the potential (within the range of potentials under which the solid remains the thermodynamically stable phase). For example, solubility of gold in high-temperature water is observed to be almost an order of magnitude higher when the redox potential is controlled using a highlyoxidizing Fe3O4-Fe2O3 redox buffer than with a moderately-oxidizing Ni-NiO buffer.[5]


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Solubility (metastable) also depends on the physical size of the crystal or droplet of solute (or, strictly speaking, on the specific or molar surface area of the solute). For quantification, see the equation in the article on solubility equilibrium. For highly defective crystals, solubility may increase with the increasing degree of disorder. Both of these effects occur because of the dependence of solubility constant on the Gibbs energy of the crystal. The last two effects, although often difficult to measure, are of practical importance.[citation needed] For example, they provide the driving force for precipitate aging (the crystal size spontaneously increasing with time). Temperature: The solubility of a given solute in a given solvent typically depends on temperature. For many solids dissolved in liquid water, the solubility increases with temperature up to 100 °C.[6] In liquid water at high temperatures, (e.g., that approaching the critical temperature), the solubility of ionic solutes tends to decrease due to the change of properties and structure of liquid water; the lower dielectric constant results in a less polar solvent. Gaseous solutes exhibit more complex behavior with temperature. As the temperature is raised, gases usually become less soluble in water (to minimum, which is below 120 °C for most permanent gases[7]), but more soluble in organic solvents.[6] The chart shows solubility curves for some typical solid inorganic salts (temperature is in degrees Celsius).[8] Many salts behave like barium nitrate and disodium hydrogen arsenate, and show a large increase in solubility with temperature. Some solutes (e.g., NaCl in water) exhibit solubility that is fairly independent of temperature. A few, such as cerium(III) sulfate, become less soluble in water as temperature increases. This temperature dependence is sometimes referred to as "retrograde" or "inverse" solubility.


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Occasionally, a more complex pattern is observed, as with sodium sulfate, where the less soluble decahydrate crystal loses water of crystallization at 32 °C to form a more soluble anhydrous phase.[citation needed]

The solubility of organic compounds nearly always increases with temperature. The technique of recrystallization, used for purification of solids, depends on a solute's different solubilities in hot and cold solvent. A few exceptions exist, such as certain cyclodextrins.[9]

Pressure :For condensed phases (solids and liquids), the pressure dependence of solubility is typically weak and usually neglected in practice. Assuming an ideal solution, the dependence can be quantified as:

where the index i iterates the components, Ni is the mole fraction of the ith component in the solution, P is the pressure, the index T refers to constant temperature, Vi,aq is the partial molar volume of the ith component in the solution, Vi,cr is the partial molar volume of the ith component in the dissolving solid, and R is the universal gas constant.[10]


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The pressure dependence of solubility does occasionally have practical significance. For example, precipitation fouling of oil fields and wells by calcium sulfate (which decreases its solubility with decreasing pressure) can result in decreased productivity with time. Solubility of gases Henry's law is used to quantify the solubility of gases in solvents. The solubility of a gas in a solvent is directly proportional to the partial pressure of that gas above the solvent. This relationship is written as:

where kH is a temperature-dependent constant (for example, 769.2 L·atm/mol for dioxygen (O2) in water at 298 K), p is the partial pressure (atm), and c is the concentration of the dissolved gas in the liquid (mol/L).The solubility of gases is sometimes also quantified using Bunsen solubility coefficient. In the presence of small bubbles, the solubility of the gas does not depend on the bubble radius in any other way than through the effect of the radius on pressure (i.e., the solubility of gas in the liquid in contact with small bubbles is increased due to pressure increase by Δp = 2γ/r; see Young–Laplace equation).[11] Polarity: A popular aphorism used for predicting solubility is "like dissolves like".[12] This statement indicates that a solute will dissolve best in a solvent that has a similar chemical structure to itself. This view is simplistic, but it is a useful rule of thumb. The overall solvation capacity of a solvent depends primarily on its polarity.[13] For example, a very polar (hydrophilic) solute such as urea is very soluble in highly polar water, less soluble in fairly polar methanol, and practically insoluble in non-polar solvents such as benzene. In contrast, a non-polar or lipophilic solute such as naphthalene is insoluble in water, fairly soluble in methanol, and highly soluble in non-polar benzene.[14] The solubility is favored by entropy of mixing and depends on enthalpy of dissolution and the hydrophobic effect. Synthetic chemists often exploit differences in solubilities to separate and purify compounds from reaction mixtures, using the technique of liquidliquid extraction.


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Rate of dissolution Dissolution is not always an instantaneous process. It is fast when salt and sugar dissolve in water but much slower for a tablet of aspirin or a large crystal of hydrated copper(II) sulfate. These observations are the consequence of two factors: the rate of solubilization (in kg/s) is related to the solubility product and the surface area of the material. The speed at which a solid dissolves may depend on its crystallinity or lack thereof in the case of amorphous solids and the surface area (crystallite size) and the presence of polymorphism. Many practical systems illustrate this effect, for example in designing methods for controlled drug delivery. Critically, the dissolution rate may depend on the presence of mixing and other factors that determine the degree of undersaturation in the liquid solvent film immediately adjacent to the solid solute crystal. In some cases, solubility equilibria can take a long time to establish (hours, days, months, or many years; depending on the nature of the solute and other factors). In practice, it means that the amount of solute in a solution is not always determined by its thermodynamic solubility, but may depend on kinetics of dissolution (or precipitation). The rate of dissolution and solubility should not be confused as they are different concepts, kinetic and thermodynamic, respectively. The solubilization kinetics, as well as apparent solubility can be improved after complexation of an active ingredient with cyclodextrin. This can be used in the case of drug with poor solubility.[15] Quantification of solubility Solubility is commonly expressed as a concentration, either by mass (g of solute per kg of solvent, g per dL (100mL) of solvent, molarity, molality, mole fraction, or other similar descriptions of concentration. The maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions. The advantage of expressing solubility in this manner is its simplicity, while the disadvantage is that it can strongly depend on the presence of other species in the solvent (for example, the common ion effect).


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Solubility constants are used to describe saturated solutions of ionic compounds of relatively low solubility (see solubility equilibrium). The solubility constant is a special case of an equilibrium constant. It describes the balance between dissolved ions from the salt and undissolved salt. The solubility constant is also "applicable" (i.e., useful) to precipitation, the reverse of the dissolving reaction. As with other equilibrium constants, temperature can affect the numerical value of solubility constant. The solubility constant is not as simple as solubility, however the value of this constant is generally independent of the presence of other species in the solvent. The Flory-Huggins solution theory is a theoretical model describing the solubility of polymers. The Hansen Solubility Parameters and the Hildebrand solubility parameters are empirical methods for the prediction of solubility. It is also possible to predict solubility from other physical constants such as the enthalpy of fusion. The partition coefficient (Log P) is a measure of differential solubility of a compound in a hydrophobic solvent (octanol) and a hydrophilic solvent (water). The logarithm of these two values enables compounds to be ranked in terms of hydrophilicity (or hydrophobicity).

1. APPLICATION Solubility is of fundamental importance in a large number of scientific disciplines and practical applications, ranging from ore processing, to the use of medicines, and the transport of pollutants.Solubility is often said to be one of the "characteristic properties of a substance," which means that 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. For example, indigo is described as "insoluble in water, alcohol, or ether but soluble in chloroform, nitrobenzene, or concentrated sulfuric acid".[citation needed] Solubility of a substance is useful when separating mixtures. For example, a mixture of salt (sodium chloride) and silica may be separated by dissolving the salt in water, and filtering off the undissolved silica. The synthesis of chemical compounds, by the milligram in a laboratory, or by the ton in industry, both make use of the relative solubilities of the desired product, as well as unreacted starting materials, byproducts, and side products to achieve separation. Another example of this is the synthesis of benzoic acid from 312 Available on www.ijrrpas.com

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phenylmagnesium bromide and dry ice. Benzoic acid is more soluble in an organic solvent such as dichloromethane or diethyl ether, and when shaken with this organic solvent in a separatory funnel, will preferentially dissolve in the organic layer. The other reaction products, including the magnesium bromide, will remain in the aqueous layer, clearly showing that separation based on solubility is achieved. This process, known as liquid-liquid extraction, is an important technique in synthetic chemistry. 2. SOLUBILITY OF IONIC COMPOUNDS IN WATER Some ionic compounds (salts) dissolve in water, which arises because of the attraction between positive and negative charges (see: solvation). For example, the salt's positive ions (e.g. Ag+) attract the partially-negative oxygens in H2O. Likewise, the salt's negative ions (e.g. Cl−) attract the partially-positive hydrogens in H2O. Note: oxygen is partially-negative because it is more electronegative than hydrogen, and vice-versa (see: chemical polarity). AgCl(s)

Ag+(aq) + Cl−(aq)

However, there is a limit to how much salt can be dissolved in a given volume of water. This amount is given by the solubility product, Ksp. This value depends on the type of salt (AgCl vs. NaCl, for example), temperature, and the common ion effect. One can calculate the amount of AgCl that will dissolve in 1 liter of water, some algebra is required. Ksp = [Ag+] × [Cl−] (definition of solubility product) Ksp = 1.8 × 10−10 (from a table of solubility products) [Ag+] = [Cl−], in the absence of other silver or chloride salts, [Ag+]2 = 1.8 × 10−10 [Ag+] = 1.34 × 10−5 313 Available on www.ijrrpas.com

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The result: 1 liter of water can dissolve 1.34 × 10−5 moles of AgCl(s) at room temperature. Compared with other types of salts, AgCl is poorly soluble in water. In contrast, table salt (NaCl) has a higher Ksp and is, therefore, more soluble. Soluble

Insoluble Carbonates (Except Group I, NH4+ and uranyl

+

Group I and NH4 compounds

compounds) Sulfites (Except Group I and NH4+ compounds)

Nitrates

+

Acetates (Ethanoates) (Except Ag compounds)

Phosphates (Except Group I and NH4+ compounds)

Chlorides (Chlorates and Perchlorates), bromides and iodides Hydroxides and oxides (Except Group I, NH4+, (Except Ag+, Pb2+, Cu+ and Hg22+)

+

2+

2+

Ba2+, Sr2+ and Tl +)

2+

2+

Sulfates (Except Ag , Pb , Ba , Sr and Ca )

3.

Sulfides (Except Group I, Group II and NH4+ compounds)

SOLUBILITY OF ORGANIC COMPOUNDS :The principle outlined above under polarity, that like dissolves like, is the usual guide to solubility with organic systems. For example, petroleum jelly will dissolve in gasoline because both petroleum jelly and gasoline are non-polar hydrocarbons. It will not, on the other hand, dissolve in ethyl alcohol or water, since the polarity of these solvents is too high. Sugar will not dissolve in gasoline, since sugar is too polar in comparison with gasoline. A mixture of gasoline and sugar can therefore be separated by filtration, or extraction with water.


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SOLUBILITY IN NON AQUEOUS SOLVENTS: Most publicly available solubility values are those for solubility in water.[16] The

reference also lists some for non-aqueous solvents. Solubility data for non-aqueous solvents is currently being collected via an open notebook science crowd sourcing project.[17][18] 5.

SOLID SOLUTION: This term is often used in the field of metallurgy to refer to the extent that an alloying element will dissolve into

the base metal without forming a separate phase. The solubility line (or curve) is the line (or lines) on a phase diagram that give the limits of solute addition. That is, the lines show the maximum amount of a component that can be added to another component and still be in solid solution. In the solid's crystalline structure, the 'solute' element can either take the place of the matrix within the lattice (a substitutional position, for example: chromium in iron) or take a place in a space between the lattice points (an interstitial position, for example: carbon in iron).19In microelectronic fabrication, solid solubility refers to the maximum concentration of impurities one can place into the substrate. DISSOLUTION INTRODUCTION Dissolution is defined as a process by which a solid substance enters in the solvent Whereas dissolution rate be defined as “the amount of drug substance that goes into the solution per unit under standardized condition of liquid/solid interface, temperature and solvent composition. Dissolution testing of poorly soluble compounds in immediate-release (IR) solid dosage forms poses many challenges. These challenges include developing and validating the test method, ensuring that the method is appropriately discriminatory, and addressing the potential for an in vivo–in vitro relationship (IVIVR) or correlation (IVIVC). The objectives of dissolution testing, in general, vary during the life cycle of a dosage form. The primary objective during Phases 0 and I is to develop a method to clearly establish the mechanism of in vitro drug release and solubilization. During Phases II and III, the objective shifts to identifying. a test method that can provide an IVIVR, IVIVC, or other bio relevant information. It is preferable to identify a dissolution test method that can evaluate both product consistency and bioavailability. This goal, however, remains a significant challenge for pharmaceutical formulation and analytical scientists, and frequently is not achievable.20


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1. CLASSIFYING DRUGS ACCRODING TO DISSOLUTION & PERMIABILITY PROPERTIES , MECHANISM OF DISSOLUTION The dissolution test determines the cumulative amount of drug that goes into solution as a function of time. As shown in Figure 1, dissolution of drug from a dosage form involves at least two consecutive steps: liberation of the solute or drug from the formulation matrix (disintegration), followed by dissolution of the drug (solubilization of the drug particles) in the liquid medium. The overall rate of dissolution depends on the slower of these two steps. The relative difference in rates should be carefully considered when designing the dissolution method. The cohesive properties of the formulated drug play a key role in the first step of dissolution. For solid dosage forms, these properties include disintegration and erosion; whereas for semisolid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor. If the first step of dissolution is rate limiting, then the rate of dissolution is considered to be disintegration controlled. Careful assessment of the intrinsic rate of dissolution and the effect of various aspects of the formulation (e.g., release profiles from precompressed granules, impact of compression force, porosity, and lubrication) can reveal the relative contribution of the disintegration step to the overall dissolution of the drug form.


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In the second step of dissolution—solubilization of the drug particles—the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical (e.g., amorphous or polymorph, and primary particle size) play an important role. If this latter step is rate limiting, then the rate of dissolution is intrinsic dissolution controlled. This is the case for most poorly soluble compounds in IR formulations. For poorly soluble compounds in solubilized formulations, in vivo precipitation also may need to be considered when developing a dissolution test method, in particular for establishing an IVIVR or IVIVC. Theories of Drug Dissolution: Dissolution is a process in which a solid substance solublizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Several theories to explain drug dissolution have been proposed some of the important one’s are… 

Diffusion layer model /film theory.



Danckwert’s model/penetration (or) surface renewal theory.



Interfacial barrier model/double barrier (or) limited solvation theory.

1. Diffusion layer model /film theory:

According to Noyes-Whitney’s Equation:

dc/dt =k s(cs-c) ---------------------------------- (1) 317 Available on www.ijrrpas.com

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Where dc/dt= Dissolution rate of the drug K= Dissolution rate Constant Cs = Concentration of drug in the stagnant layer C = Concentration of drug in the bulk of the solution at time t S =Surface area of the particles When a solid is introduced into the dissolution medium, the volume of fluid immediately adjacent to its solid surface gets saturated with the drug. The thin stationary film of solution around the solid surface is called diffusion layer the concentration in this layer is equal to cs. The thickness of the diffusion layer is ‘h’ .The dissolution rate constant rate can be expressed as K= D/h

-----------------------(2)

Where D = Diffusion coefficient of the drug in solution H = Thickness of the diffusion layer Equn (1) changes: Dc/dt = Ds/h (cs-c) ------------------(3) As the drug continuously diffuses from the diffusion layer into the bulk layer, more and more of drug release from the solid into the diffusion layer. The concentration of a drug in the bulk ‘c’ will be always less Compared to its concentration in the diffusion layer (cs). The term (cs-c) represents the concentration gradient between the diffuse layer and bulk Solution. In equn (3), the concentration gradient (csc) is variable and other terms are constant. Equn (3) describes a first order dissolution kinetics. If the concentration is plotted against time, a curvilinear plot is obtained.


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First order kinetic plot If the log concentration is plotted against time, a straight line is obtained. The slope of this line gives the dissolution rate constant.

First order plot (semi log) It is also possible to plot log percent-undissolved vs time. As the dissolution proceeds, the amount remaining undissolved decreases. So negative slope is obtained .The dissolution rate constant is estimated as slope x 2.303.


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First order plot (amount of drug remain undissolved vs time) (These above plots represents dissolution rate under non-sink conditions) In the dissolution process’s’ can be considered negligible compared to cs, if the volume of dissolution medium is large excess, i.e. sink conditions. Then equn (3) can be written as: dc/dt =DS/h cs ------------------------(4) Where dc/dt= Dissolution rate of the drug cs = Concentration of drug in the stagnant layer D = Diffusion coefficient of the drug in solution H = Thickness of the diffusion layer s =Surface area of the particles In the equn (4), the terms D, S, h & cs are constants. Hence equn (4) follows zero order, i.e.…a constant dissolution rate under sink conditions. The zero order kinetic process i.e.. a linear plot is represented


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In the equn (4),h and s are considered as constants, but this is not the case always. The diffusion layer thickness, h is altered by the force of agitation at the surface of the solid or tablet. Similarly, surface area A, also changes Continuously as the powder or the granules or tablet dissolves. Therefore it is difficult to obtain an accurate measurement of h and s. 2. Danckwert’s model/penetration (or) surface renewal theory.

Danckwert’s apposed the existence of stagnant layer by assuming that turbulence in the dissolution medium exists at the solid/liquid interface. He suggested that the agitated fluid contains macroscopic mass of eddies (or) packets reach the solid/liquid interface in a random fashion due to eddy currents, absorb the solute by diffusion and carry it to the bulk of the solution. Such solute containing packets are 321 Available on www.ijrrpas.com

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continuously replaced with new packets of fresh solvent due to which the drug concentration at the solid/liquid interface never reaches cs and has a lower limiting of ci.since the solvent packets are exposed to new solid surface each time, this theory is also called surface renewal theory Danckwert’s model is expressed by equn

V dc/dt = dm/dt = A (Cs-Cb). (γD) ½

Where V=volume of dissolution medium. dc/dt=dissolution rate of the drug. m=mass of solid dissolved. A=surface area of the dissolving solid. Cs = Concentration of drug in the stagnant layer. Cb = Concentration of drug in the bulk of the solution at time t. D=diffusion coefficient (diffusivity) of the drug. γ = rate of surface renewal(or)the interfacial tension. 3.Interfacial barrier model/double barrier (or) limited solvation theory. The diffusions layer model and Danckwerts model are based on two assumptions. 1.Rate determining step that contains dissolution in the mass transport. 2.solid-soln equilibrium is achieved at the soild liquid interface. According to the interfacial barrier model: An intermediate concentration can exist at the interface as result of solvation mechanism and function of solubility rather than diffusion. When considering the dissolution of a crystal, each face of the crystal will have a different interfacial barrier such a concept is given by the following equn. G=Ki(cs-cb) where 322 Available on www.ijrrpas.com

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G=dissolutionte rate per unit area Ki =effective interfacial transport constant. Cs = Concentration of drug in the stagnant layer Cb =Concentration of drug in the bulk of the solution at time t In this theory, the diffusity D may not be independent of saturation concentration cs. Therefore the interfacial model can be extended to both diffusion layer model and Danckwerts model. Study of various approaches to improve the dissolution of Drugs: As we all know that dissolution is the rate-limiting step in absorption of most drugs, the attempts whether optimizing the formulation, manufacturing process (or) physico-chemical properties of the drug are mainly aimed at enhancement of dissolution rate. the effective surface area of the drugs are discussed below 

Micronization



Use of a surfactant



Use of a salt forms



Use of metastable polymorphs



Solute-solvent complexation /solvates



Solvent deposition



Selective adsorption on insoluble carriers



Solid dispersion

Some of the widely used methods, most of which are aimed at increasing

.

1.solid soln 2.glass soln 3.eutetic mixtures


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Micronization The process involves reducing the size of the drug particles to 1-10 µ’s which is commonly done by spray drying (or) by use of air attrition methods (fluidized bed dryer).As the Micronization process proceeds the size of the particles decreases and the effective surface area increases From the modified Noyes-Whitney’s Equation dc/dt ά A i.e.…the rate of dissolution is directly proportional to surface area, hence by micronization the effective surface area increases there by increasing the dissolution rates ,this is practically true in case of drugs which are non-hydrophilic. Eg: Micronization of poorly aqueous soluble drugs like griseofulvin, choramphenicol, several steroids, sulpha drugs enhances its dissolution. Micronization has reduced the dose of griseoflulvin to half and also spironolactone was decreased by 20 times. In case of hydrophobic drugs like Aspirin, phenacetin, phenobabarbital. Micronization results in fall in the dissolution rate because of decreases in effective surface area because of the reasons. 1.The hydrophobic surface of the drug adsorb air on their surface which inhibit their wettability such powders float on the surface of dissolution medium. 2.Due to their high surface free energy, the particles segregate to form larger particles, which either float on the surface or settle at the bottom of the dissolution medium. 3.Size reduction may impart surface charges to the particles, which may prevent wetting. Surfactants: The surface active agents enhances dissolution rate primarily by promoting wetting and penetration of dissolution fluid into the solid drug particles .Non-ionic surfactants like polysorbates are widely used. Generally used in concentration below cmc, since above cmc the drug entrapped in the micelle structure fails to partition in the dissolution fluid. Ex: tween-80 increases the dissolution of phenacetin by promoting its wettability. Salt forms: Formation of salt form of the drugs has improved solubility & dissolution characterstics in comparisation to the original drug. 324 Available on www.ijrrpas.com

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In case of weak acid with increase in pH of the diffusion layer & dissolution is enhanced where as in case of weakly basic drugs decrease in pH of the diffusion layer dissolution is enhanced. Ex: Alkali metal salts of acidic drugs like penicillin's & strong acids salts of basic drugs like atropine are more water-soluble than the parent drug. Metastable

polymorphs Depending on the relative stability of different solid forms of drugs one of the several polymorphic forms will

be physically more stable than the others such a stable polymorphs represents low energy state has highest melting point and least aqueous solubility.Remaining polymorphs are called as metastable forms, which represent the higher energy state, have lower m.p, high solubility.

Since the metastable forms have greater solubility they show good dissolution rates and are therefore preffered in

formulations.Order for dissolution of different solid forms drugs is Amorphous>metastable>stable Ex: Among the 3 polymorphic forms of chloramphenical palmitate A, B, C Form B shows best dissolutions & bioavailability where as form A is virtually inactive. The polymorphic form iii of riboflavin is 20 times more water-soluble than form i. Solute-Solvent complexation solvates The crystalline form of the drug can either be a polymorph or a molecular adducts or both. Those adducts where the solvent molecules are incorporated into the crystal lattice of the solid are called as solvates & the trapped solvent as the solvent of crystallization.When the solvent associated with the drug in water the solvent is known as hydrate. Hydrates are most common forms of drugs. Generally the anhydrous form of a drug shows greater aqueous solubility than the hydrates. This is because the hydrates are already in interaction with water molecules and therefore have a less energy for the crystal break up in comparison to the anhydrates. Ex: The anhydrous forms of theophylline & ampicillin are higher aqueous solubility's, dissolves at a faster rate & show better bioavailability in comparison with their monohydrate & trihydrate forms respectively. On the other hand the organic (non organic) solvates are greater aqueous solubility than the non-solvates. Ex: N-pentanol, solvate of fludrocortisone & succinyl sulphathiazole chloroform solvate of grisefolvin.


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Solventdeposition In this method, poorly aqueous soluble drug such as nifedipine is dissolved in an organic solvent like alcohol and deposited on an inert hydrophilic solid matrix such as starch (or) mcc by evaporation of solvent. As the dissolution begins the drug particles deposited on the inert solid matrix dissolves with it and hence dissolution is faster & better bioavailability. Selective adsorption on insoluble

carriers:Here highly active adsorbents such as inorganic clays like bentonite can enhance the

dissolution rate of poorly water-soluble drugs such as griseofulvin, indomethacin & prednisolone. The drug particles are made to deposit on the bentonite and the rapid release of the drug from the surface of the clays occurs due to the weak physical bonding between the adsorbate & adsorbent and hydration and swelling of the clay in the aqueous media. Solid dispersion Here a particle size can be reduced to a sub micron level to enhance the solubility of hydrophobic drug. 1.Solid solution 2.Glass solution 3.Eutetic mixtures Solid solution Solid solution is made up of a solid solute dissolved in a solid solvent and it often called as mixed crystals because the two components crystallize together in a homogeneous phase system. Solid soln of a poorly soluble drug in a rapidly soluble carriers achieves a faster dissolution rate than eutectic mixture because the particle size in the solid soln is reduced to a minimum state i.e....molecular size. E.g.: grisefulvin –succinic acid Digitoxin-peg 6000. Ibuprofen-peg 4000/6000 Frusemide –peg4000/6000(1:1)


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Glass solution When solid solution formed in a homogenous transparent and brittle system it is called as glass solution. Carriers that form glossy structure upon cooling are citric acid, urea, pvp, peg and sugar such as sucrose and galactose.strength of the chemical binding in a glass soln is much less compared to that in a solid soln. Hence dissolution rate of drugs in the glass soln is faster than in solid soln. Eutectic mixtures Eutectic mixtures are prepared by rapid solidification of the fused liquid of two components, which show complete liquid miscibility and negligible solid-solid solubility When eutectic mixtures composed of poorly soluble drugs is exposed to water (or) g.i. Fluid the carrier gets released into the aqueous media leaving the drug in fine crystalline form whose surface area is large due to reduction in particle size. Eg: Parcetamol-urea Griseofulvin-urea. In-vitro dissolution testing models Characterizing the drug-release mechanism by establishing an in vitro dissolution test method (or an appropriate alternative method) to measure product performance is particularly important for poorly soluble compounds. Dissolution testing historically has been a key tool during the development stages of a compound as well as for commercial manufacturing. For a development compound, dissolution testing is used primarily to help develop and evaluate new formulations by evaluating the rate of drug release from dosage forms, evaluating the stability of these formulations, monitoring product consistency, assessing formulation changes, and establishing IVIVRs or IVIVCs. For a commercial product, dissolution testing is used primarily to confirm manufacturing and product consistency, to evaluate the Quality of the product during its shelf life, and to assess postapproval changes and the need for bioequivalency studies. A dissolution test measures the rate of release of the drug. The objective is to develop a discriminatory method that is sensitive to variables that affect the dissolution rate. Such variables may include characteristics of the active pharmaceutical ingredient (API) (e.g., particle size, crystal form, and bulk density), drug product composition (e.g., drug loading, and the identity, type, and levels of excipients), the drug product manufacturing process (e.g., compression conditions (e.g., temperature, humidity). Although it also is desirable to develop a dissolution test that establishes an IVIVC or an IVIVR, that kind of correlation between observed changes in in vitro dissolution rate to meaningful in vivo product performance quality remains a key challenge. 327 Available on www.ijrrpas.com

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Dosage form type and design affect dissolution testing These key compound properties of dissolution, solubility, and permeability (along with other factors such as dose, bioavail-ability, stability, and process ability) will dictate the formulation design of a new product. In turn, considering the formulation design and mechanism of drug release from the product is critical in developing a dissolution test method. In the case of intrinsic dissolution-limited absorption (i.e., the disintegration of the dosage form is rapid, but dissolution is slow) a formulation approach commonly used is to reduce the particle size of the API. Small particle size, however, creates challenges in developing a dissolution test method. Small particles (e.g., in formulations in which the drug is milled down to nanometer dimensions) can pass through filters and subsequently dissolve. In these cases, the use of smaller-pore filters, centrifugation, ultra centrifugation, or high wavelength UV detection may be needed. In addition, as the saturation solubility in the dissolution test media approaches 1X (defined as the solubility limit), small variations in assay parameters have an increasing effect on dissolution assay variability. Also, in the case of solubility-limited absorption (intrinsic solubility controlled), a formulation approach commonly used is to enhance the transient solubility of the API. This approach includes using different salt forms of the API, using surfactants in the formulation, using solubilized liquid formulations in hard or soft gelatin capsules, and using noncrystalline materials. With transient solubility enhancement, one may have to consider that there may be a kinetic trade off between absorption and precipitation in vivo. In the case of disintegration controlled absorption, the compound has a better solubility profile, but the two steps of dissolution may be competing and be very similar to each other. In either case, understanding the two steps of drug dissolution and which one is a rate-limiting aid in designing the dissolution test (e.g., media selection). Dissolution test design Before human clinical studies are conducted, dissolution data usually must be generated without the benefit of comparative rankings between formulations or lots, estimated in vivo human absorption rates, or any other information that could guide the development of a discriminating dissolution test. When developing a dissolution test for poorly soluble compounds early in drug


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development, therefore, the process should focus on assessing relevant physical and chemical properties of the API and the drug product’s dosage form design, because these will guide the choice of the dissolution medium and apparatus. This strategy for designing a dissolution test will change, however, in later stages of drug development, because of the evolving purpose of the dissolution test as well as the availability of additional data. For example, with the accumulation of both in vivo and in vitro experience during a product’s development cycle, the early-phase dissolution test method should be critically reevaluated and potentially simplified for final QC testing. And in some cases, the data acquired will demonstrate the usefulness of alternative methods to replace dissolution testing. As the data become available for IR formulations that contain Class I drugs (e.g., if the 85% of the drug dissolves in 15 min in pH 1.2, 4.5, and 6.8 buffers), a disintegration method can be justified and substituted for a dissolution test. Media selection The choice of medium will depend on the purpose of the dissolution test. For batch-to-batch quality testing, selection of the dissolution medium is based, in part, on the solubility data and the dose range of the drug product to ensure that sink conditions are met. The term sink conditions is defined as the volume of medium at least greater than three times that required to form a saturated solution of a drug substance. A medium that fails to provide sink conditions may be justifiable, however, if it is shown to be more discriminating or if it provides reliable data which otherwise can only be obtained with the addition of surfactants. On the other hand, when the dissolution test is used to indicate the biopharmaceutical properties of the dosage form, it is more important that the proposed bio relevant test closely simulate the environment in the gastrointestinal (GI) tract than necessarily produce sink conditions.the dissolution characteristics of oral formulations should first be evaluated using test media within the physiologic pH range of 1.2–6.8 (1.2–7.5 for modified-release formulations) because low-solubility drugs include those with adequate aqueous solubility at either acidic (e.g., amines) or neutral (e.g., organic acids) pH levels. During method development, it may be useful to measure the pH of the test medium before and after a run to see if the pH changes during the test. Selecting the most appropriate medium for routine QC testing is based on discriminatory capability, ruggedness, stability of the analyte in the test medium, and relevance to in vivo product performance where possible. Aqueous media without any surfactants are preferred, but aqueous media with surfactants may be used to increase the probability of establishing an in vivo relationship.


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For some low-solubility compounds, adequate dissolution cannot be obtained with aqueous solutions within physiologic pH ranges. For these compounds, an aqueous solution containing a surfactant may be used to enhance drug solubility. Commonly acceptable ionic or nonionic

surfactants

include

sodium

lauryl

sulfate

(SLS),

polyoxyethylenesorbitan

monolaurate

(Tween),

cetyltrimethylammoniumbromide (CTAB), polyoxyl castor oil (Cremophor), hexadecyltrimethylammonium bromide (HTAB), polyethylene glycol tert-octylphenyl ether (Triton), nonylphenol ethoxylate (Tergitol), cyclodextrins, and lecithin. In general, nonionic detergents (e.g., Tween) are considered more biologically relevant, and thus are often the first choice when considering the addition of a surfactant. A surfactant can be used as either a wetting agent or, when the critical micelle concentration (CMC) is reached, to solubilize the drug substance. The need for surfactants, as well as their type and concentration, should be justified. The amount of surfactant needed for adequate drug solubility depends on the surfactant’s CMC and the degree to which the compound partitions into the surfactant micelles. The surfactant’s CMC depends, in turn, on the surfactant itself and the ionic strength of the base medium. Because of the nature of the compound and micelle interaction, typically a linear dependence exists between solubility and surfactant concentration above the CMC. If a compound is ionizable, surfactant concentration and pH may be varied simultaneously, and the combined effect can substantially change the solubility characteristics of the dissolution medium. Using an aqueous-organic solvent mixture as dissolution medium is discouraged; however, if an IVIVR or IVIVC is demonstrated that cannot be accomplished with a purely aqueous medium, an aqueous-organic solvent may be considered. The acceptability of such an aqueous-organic solvent media based dissolution method should be discussed with regulatory agencies early in product development.21

Apparatus selection : Physical and chemical properties of the API (e.g., solubility and stability) as well as the formulation concept play a key role in selection of the dissolution test apparatus, especially for poorly soluble compounds. Dissolution testing is conducted on equipment that has demonstrated suitability, such as that described in the United States Pharmacopeia (USP) under the general chapters of Dissolution& and Drug Release. The basket method (USP Apparatus 1) is routinely used for solid oral dosage forms such as capsules or tablets at an agitation speed of 50 to 100 rpm, although speeds of up to 150 rpm have been used. The paddle method (USP Apparatus 2) also is used frequently for


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solid oral dosage forms such as tablets and capsules, but at 50 or 75 rpm. Both the paddle and the basket methods can accommodate media volumes ranging from 500 to 1000 mL with the standard vessel and 2000 to 4000 mL with larger vessels. Higher vessel volumes can be advantageous for low-solubility compounds. For highly potent, low dosage drugs, the use of 100 to 250 mL vessels should be explored. The reciprocating cylinder (USP Apparatus 3) and the flow through cell (USP Apparatus 4) also may offer advantages for some low-solubility dosage forms. Apparatus 3 can be used to estimate the drug release profile in the GI tract by using a series of different media in the vessels. Apparatus 4 may be more useful if certain ruggedness aspects can be improved by the vendors. By design, both the reciprocating cylinder and the flow through cell allow for a controlled pH and volume change of the dissolution medium throughout the test. However, USP Apparatus 3 and 4 or other modified configurations are most often limited to use in product development and characterization. Flexibility in the selection of the apparatus during development facilitates understanding of the dissolution mechanism. Once the dissolution mechanism is understood, attention is focused on developing a method that is compendially acceptable and that may demonstrate an IVIVR or IVIVC. The superiority of a new or modified apparatus design should be proven in comparison to the compendial apparatus. The effect of hydrodynamics such as speed, axial velocity, vessel contours, currents, eddies, surface area, positioning, paddle shape, cage, and sinkers, should be considered during method development.


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Dharmendra singet al, IJRRPAS, 2(2).305-341, Apparatus no

IP

BP

USP

Type 1

Paddle

Basket

Roating Basket

Type 2

Basket

Paddle

Paddle

3

Flow

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through Reciprocating cylinder

cell

Flow through cell Paddle over disc Rotating cylinder Reciprocating disc

Classification of dissolution testing models Paddle type:

I.P type I, B.P type II, U.S.P TYPE II


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Official

Medium

Standard

Modification

Uses

Rpm 25-150

Solids, modified release

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book I.P 96

As

mentioned

in

individual

Teflon steel

monographs

stainless paddle

tablets. Edge of

1000ml

Blade:25-27mm B.P 2005

As

mentioned

in

Teflon

individual

steel

monographs

1000ml

stainless paddle

Shaft

position

within

2mm of the axis of

Solids, modified release tablets

vessel. Lower edge of blade 2327mm

U.S.P2000

As

mentioned

in

Teflon

stainless

100-400ml,surfactant in


individual

steel

media,pH change during

tablets,transdermal

monographs

paddle,900ml

test.

patch

,wire sinker or


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floaters U.S.P2000

As

mentioned

in

individual monographs

Teflon

100-400ml,surfactant in


steel

media,pH change during

tablets,transdermal

paddle,900ml

test.

patch

,wire

stainless

sinker

or

floaters

Rotating basket type: I.P type II,B.P type I, U.S.P type I.


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Dharmendra singet al, IJRRPAS, 2(2).305-341, Official book

Medium

I.P 96

As in

Standard

mentioned 40mesh

Modification

Uses

----------

Microspheres,

individual stainless steel,

monographs

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controlled

Capacity

release,

1000ml

capsules, tablets etc…

B.P 2005

As in

mentioned 40mesh,for

As in

Microspheres,

individual acidic media a

monographs

U.S.P2000

----------

thin

controlled

gold

release,

coated layer of

capsules,

25m

tablets etc…

mentioned 40mesh

10-100

mesh, Solids, floaters,

individual stainless steel, 100-4000ml

monographs

Capacity 900ml

beads, modified

volume, basket release dosage dimensions, pH forms. change during test.

Classification of U.S.P apparatus: 1.Flow through cell 2.Reciprocating cylinder 3.Paddle over disc 4.Rotating cylinder 5.Reciprocating disc 335 Available on www.ijrrpas.com

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Flow through cell:

It consists of dissolution reservoir for the dissolution medium and a pump forcing dissolution medium through the cell that holds the test sample flow rate ranges from4-16 ml/min. six samples are tested during the dissolution testing and the medium is maintained at 37 c. use: modified release dosage forms that contain active ingredients having very limited solubility. Official book B.P 2005

Medium

Standard

Modification

As mentioned in

Temp: 36.5-37.5 c,

1.Reservior

individual

glass beads size 0.9-

dissolution medium.

monographs

1.1 mm, flow of dissolution

at

specific rate.

Uses for

Low

solubility

drugs,

drug

undergoing 2.pump

degradation,

3.Thermostatically

media including

controlled

pH change

flow

through cell and filter U.S.P2000

As mentioned in

Temp: 36.5-37.5 c,

Size, flow rate filter

Low

individual

glass beads size 0.9-

open/closed cell

drugs,

monographs

1.1 mm, flow of

undergoing

dissolution

degradation,

at

specific rate

solubility drug

media including pH change


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Reciprocating cylinder:

•Sequential media tube: Typical volume 200ml •Modification: Size, volume, no of rows •Temp maintained at 37 c •Use: pH profile beads, sustained release dosage forms. It consists of a set of cylinder flat bottom glass vessel equipped with reciprocating cylinder for dissolution testing reciprocating cylinder with mesh screen at top and bottom.

Paddle over disc:


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Paddle over disc consists of a sample holder or a disc assembly that’s holds the product. The entire preparation is placed in a dissolution flask filled with a specified medium at temp 32 c .The paddle is placed directly over the disc dissolution flask filled with specified assembly. Sample is drawn mid way between the surfaces of the dissolution medium and the top of the paddle blade at specified times. Similar

to

dissolution

testing

with

capsules

and

tablets

six

units

are

tested

during

each

time.

Standard paddle is used Volume: 900ml Modifications: disc design Uses: Transdermal patches, floatters. Rotating cylinder:

It is modified from basket type. In the place of basket a stainless steel cylinder is mounted the sample is mounted and the entire system is adhere to the cylinder. Testing is maintained qt temp 32 c. samples are drawn mid way between the surface of the dissolution medium andthetopoftherotatingcylinder. •Special cylinder used •Typical volume: 900 ml •Used: Transdermal patches. 338 Available on www.ijrrpas.com

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Reciprocating disc:

A motor drive assembly us used to reciprocate the system vertically and the samples are placed on disc shaped holders using cuprophan supports. The test is also carried at 32 c and reciprocating frequency is about 30 cycles/min. Standards: Sample holder Sequential media tube Typical volume: 50-400 ml Modification: volume: 20-200 ml ,Dosage form holder.22


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References 1.

Yuen, C. (2003)). Element, Compound and Mixture.

2.

Clugston M. and Fleming R. (2000). Advanced Chemistry (1st ed.). Oxford: Oxford Publishing. p. 108.

3.

"Cancerweb.ncl.ac.uk: from Online Medical Dictionary, University of Newcastle Upon Tyne". http://cancerweb.ncl.ac.uk/cgi-bin/omd?metastable.

4.

IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific

Publications, Oxford (1997). XML on-line corrected version: http://goldbook.iupac.org (2006-) created by M. Nic, J. Jirat, B. Kosata; updates compiled by A. Jenkins. ISBN 0-9678550-9-8. doi:10.1351/goldbook. Entry: Solubility. 5.

I.Y. Nekrasov (1996). Geochemistry, Mineralogy and Genesis of Gold Deposits. Taylor & Francis. pp. 135–136. ISBN 9789054107231.

http://books.google.ca/books?id=HUWRZecignoC&pg=PA135#PPA135,M1. 6.

John W. Hill, Ralph H. Petrucci, General Chemistry, 2nd edition, Prentice Hall, 1999.

7.

P. Cohen, ed (1989). The ASME handbook on Water Technology for Thermal Power Systems. The American Society of Mechanical Engineers. p. 442.

8.

Handbook of Chemistry and Physics (27th ed.). Cleveland, Ohio: Chemical Rubber Publishing Co.. 1943.

9.

Salvatore Filippone, Frank Heimanna and André Rassat (2002). "A highly water-soluble 2+1 b-cyclodextrin–fullerene conjugate". Chem. Commun.

2002: 1508–1509. doi:10.1039/b202410a. 10. E.M.Gutman (1994). Mechanochemistry of Solid Surfaces. World Scientific Publishing Co.. 11. G.W. Greenwood (1969). "The Solubility of Gas Bubbles". Journal of Material Science 4: 320–322. doi:10.1007/BF00550401. 12. Kenneth J. Williamson (1994). Macroscale and Microscale Organic Experiments (2nd ed.). Lexington, Mass.: D. C, Heath. p. 40. ISBN 0669194298. 13. The solvent polarity is defined as its solvation power according to Reichardt 14. Merck Index (7th ed.). Merck & Co.. 1960. 15. Gil A, Chamayou A, Leverd E, Bougaret J, Baron M, Couarraze G (2004). "Evolution of the interaction of a new chemical entity, eflucimibe, with gamma-cyclodextrin during kneading process". Eur. J. Pharm. Sciences 23: 123–129. doi:10.1016/j.ejps.2004.06.002. 16. "NIST solubility database". http://srdata.nist.gov/solubility/casNO.aspx. 17. "ONS Solubility challenge". http://onschallenge.wikispaces.com/. 18. "Solubility of Vanillin in various non-aqueous solvents". http://oru.edu/cccda/sl/solubility/allsolvents.php?solute=vanillin. 19. O.M.Saether & P. de Caritat, ed (1997). Geochemical processes, weathering and groundwater recharge in catchments. Rotterdam: Taylor & Francis. p. 6. ISBN 9054106417.


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20. A Text Book Biopharmaceutics and pharmacokinectics by Gibaldi 21. A Text Book of Principles and applications of Biopharmaceutics and pharmacokinectics by Dr.H.P.Tipins & Dr.Amirta Raj. 22. A Text Book of Physical Pharmaceutics by C.V.S Subrahmanyam


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