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Seminar onTECHNIQUES OF SOLUBILIZATION By V. Maheswari M. Pharm (1st semester) Pharmaceutics St. Peter’s Institute of Pharmaceutical Sciences Vidyanagar Hanamkonda , Warangal 506 001


CONTENTS INTRODUCTION IMPORTANCE OF SOLUBILIZATION TECHNIQUES OF SOLUBILIZATION Solubilization of drugs by cosolvents Alteration of solubiliy through complexation Drug solubilization in surfactant systems Solubilization by solid state manipulation Drug derivatisation as a means of solubilization 4. CONCLUSION

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INTRODUCTION: DEFINITION: Solubility is defined in quantitative terms as the concentration of solute in a saturated solution at certain temperature, and in qualitative way it can be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. Solubility is defined as the molecular dispersion of solute in the solvent. Solubilization can be defined as a the preparation of a thermodynamically stable isotropic solution of a substance normally insoluble or very slightly soluble in a given solvent by the introduction of an additional component or components.

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Process of solubilization:- The process of solubilization involves the breaking of inter-ionic or inter-molecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion. Step 1: Holes opens in the solvent

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Step 2: Molecules of the solid breaks away from the bulk Step 3: The freed solid molecule is intergrated into the hole in the solvent

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IMPORTANCE OF SOLUBILIZATION: An understanding of the solubility behavior of a drug candidate can be regarded as one of the most important aspects of preformulation testing for poorly soluble compound. For parenteral formulations, the drug must be soluble in a pharmaceutically acceptable vehicle. For oral formulations, the drug must have an adequate solubility and dissolution rate to achieve suitable bioavailability. Solubility is an important physico-chemical property of a drug. In order for a drug to enter systemic circulation and to exert a therapeutic effect it must first be in solution form.

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Terms of approximate solubility

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TECHNIQUES OF SOLUBILIZATION: Solubilization by cosolvents Solubilization in surfactant systems Alteration of solubility through complexation Solid state manipulation Drug derivatisation

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SOLUBILIZATION BY COSOLVENTS: Weak electrolytes and non polar molecules frequently have poor aqueous solubility. Their solubility in water is increased by addition of water miscible solvents in which drug has good solubility. This process is called cosolvency and the added solvents are called cosolvents. The cosolvents such as propylene glycol, polyethylene glycol, ethanol, glycerine aids to solubilise drug in aqueous vehicle. The solubilising effect by cosolvency is primarily dependent upon the polarity of drug with respect to solvent and cosolvent.

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Mechanism responsible for solubility enhancement through cosolvency is by reducing the interfacial tension (polaity differences) between the predominantly aqueous solution and hydrophobic solutes and reduces the contact angle between solid and liquid. Addition of cosolvents that reduce the difference between the polarity of the drug and water system, there by increasing solubility. Cosolvents can increase the solubility of a nonpolar drug up to several orders of magnitude compared to its aqueous solubility.

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When delivered parentally or orally, a drug in solution has more bioavailability compared to a solid dosage form. When solubilization of a drug is achieved by use of cosolvent, it must meet certain requirements, such as non toxicity, compatibility with blood, non sensitizing, non irritating, and above all physically and chemically stable and inert.

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NON POLAR SOLUTES: For non-polar compounds ,solubilization approaches 5-6 orders of magnitude.

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SEMI POLAR SOLUTES: The semipolar solutes or drugs usually have parabolic log(solubility) Vs cosolvent composition curves. The overall gain in solubility for semipolar solutes is generally less than a factor of 5, which is significantly less than that of non polar solutes.

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POLAR SOLUTES: There is a decrease in solubility of polar solutes with the addition of an organic cosolvent to water. CALCIUM OXALATE

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SOLUBILISATION BY COMPLEXATION: It is defined as the reversible association of a substrate and ligand to form a new species with a well defined stoichiometry. mS+ nL <═> SmLn Complexation relies on relatively weak forces such as ,hydrogen bonding and hydrophobic interactions.

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Stacking complexes: These are formed by the overlap of planar regions of aromatic compounds Eg: napthalene, salicylicacid, theobromine. b) Inclusion complexes: These are formed by the insertion of the nonpolar region of one molecule into the cavity of another molecule Eg: cyclodextrins

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The mathematical description for the equilibrium constant of a 1 : 1 complex, K1:1, is defined by K1:1= [SL]/[S][L] S is the concentration of free solute, L is the concentration of free ligand SL is the concentration of the solute/ligand complex.

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MICELLAR SOLUBILISATION: Surfactants are molecules with distinct polar and nonpolar regions. Most surfactants consist of a hydrocarbon segment connected to a polar group. The polar group can be anionic, cationic, zwitterionic or nonionic. When small apolar molecules are added they can accumulate in the hydrophobic core of the micelles. This process of solubilization is very important in industrial and biological processes. The presence of surfactants may lower the surface tension and increase the solubility of the drug within an organic solvent

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A simple mathematical representation for a solute’s total solubility, ST, in a surfactant system is ST =Sw + k[Csurf – CMC] General curve for solubilization with surfactants

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Accordingly, hydrophilic drugs can be adsorbed on the surface of the micelle (1), drugs with intermediate solubility should be located in intermediate positions within the micelle such as between the hydrophilic head groups of PEO micelles (2) and in the palisade layer between the hydrophilic groups and the first few carbon atoms of the hydrophobic group, that is the outer core (3), and completely insoluble hydrophobic drugs may be located in the inner core of the micelle (4)

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Insoluble drugs incorporation into micelles by: O/W Emulsion Method : This method consists first of preparing an aqueous solution of the polymer. To this add a solution of the drug in a water-insoluble volatile solvent (e.g., chloroform).The micelle-drug complex forms as the solvent evaporates.

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SOLID STATE MANIPULATION: Many compounds, especially organic molecules will naturally occur or are capable of being manipulated to exist in more than one form as solid.

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Polymorphic modifications: Solubility of each form depends upon the ability of the molecules to escape from the crystal to solvent. The stable form posses the lower free energy at a particular temperature and therefore has the lower solubility or escaping tendency where as the meta stable forms posses higher free energy hence has higher solubility. About fifty to hundred percent increase in the dissolution rate can be achieved through polymorphic modifications. Examples: Chloramphenicol palmitate (form B) Methyl prednisolone (form 2) Chlor tetracycline (form B)

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Non crystalline solutes (amorphous): As the term implies they will not contain internal crystal lattice structure. These are thermodynamicaly unstable. Amorphous solid forms give faster dissolution rates and higher solubilities than polymorphic modifications. Eg: Novobiocin Thus, the order for dissolution of different solid forms of drug is Amorphous >Metastable >Stable

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Solvates (pseudo polymorphism) The recrystallization of many drug substances from solution will results in the formation of solids containing solvent molecules as an integral part of their crystal structure. Majority of these crystalline materials referred as pseudo polymorphs, contain stoichiometric amount of solvent. Anhydrates > hydrates Organic solvates > organic non-solvates Enhances the solubility of drug markedly. Examples: pentanol solvates of fludrocortisone chloroform solvates of griseofulvin cephalexin hydrate

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Retardation of phase transformation: PVP, pectin, acacia, gelatin, methylcellulose, carboxymethyl cellulose, surfactants retard phase transformation. These materials retard phase transformation by inhibiting crystal growth by adsorbing on to the surface of nucleated crystals or by Increasing viscosity which in turn retards the diffusion control process of crystallisation. This retardation has improved physical stability of amorphous drugs by inhibiting drug crystallization by minimizing molecular mobility.

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Solid dispersions: The term solid dispersion is applied to those systems in which the dispersion of one or more active ingredients in an inert excipient or matrix(hydrophillic), where the active ingredients could exist in finely crystalline, solubilized, or amorphous states. Examples: 1. polyethylene glycols -Oxazepam, Nefidipine, Ketoprofen 2. Polyvinylpyrrolidine -Hydrochlorthiazide, Valdicoxib 3. Maltodextrins-Piroxicam Solid dispersions

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Hot Melt method Drug and carrier were melted together and then cooled in an ice bath. The resultant solid mass was then milled to reduce the particle size. but due to solidification the dispersed drug becomes trapped within the carrier matrix. A molecular dispersion can be achieved .Another important requisite is the thermostability of the drug and carrier. Solvent Evaporation Method Drug and carrier are dissolved in a common solvent and then evaporate the solvent under vacuum to produce a solid dispersion .

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Eutectic Mixtures: Phase diagram of a simple eutectic system At temperatures below curve XY or YZ, either solid A [drug] or solid B [carrier] solidifies first from the molten mixture, respectively. At eutectic composition Y, both drug and carrier solidify simultaneously as a mixture of finely divided crystalline components.

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When two materials are completely miscible in there molten state they will solidify to form a eutectic mixture. At the eutectic composition (Y), both drug and carrier exist in finely divided state, which results in higher surface area and enhanced dissolution rate of drug. The process of eutectic formation may cause the drug to crystallise in a metastable state. Urea and Succinic acid have been found to form simple eutectics with a wide variety of drugs

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DRUG DERIVATISATION AS A MEANS OF SOLUBILIZATION: Possible approaches to increase the solubility of poorly soluble drugs by the process of derivatisation Prodrug approach: Prodrug is a compound that must undergo bioconversion before exerting its pharmacological effect. The functional groups-esters, thioesters, amides, acetals, and ketals are used.

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Salt Formation: In general, aqueous solubility is a function of chemical structure, and salts represent the class of drugs that are most likely to attain the desired extent of solubility in water. The salt form of a drugs is usually more soluble than parent drug. An alkaloidal base is slightly soluble in water, but if the pH of medium is reduced by addition of acid, and the solubility of the base is increased as the pH continues to be reduced. The reason for this increase in solubility is that the base is converted to a salt, which is relatively soluble in water.

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The solubility of slightly soluble acid is increased as the pH is increased by addition of alkali, the reason being that a salt is formed (e.g. Aspirin, Theophylline, Barbiturates).

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Other methods include: Micronization: The solubility of drug is often intrinsically related to drug particle size. By reducing the particle size, the increased surface area improve the dissolution properties of the drug. Solubilizing agents: The solubility of poorly soluble drugs can also be improved by various solubilizing materials. PEG 400 is improving the solubility of hydrochlorthiazide. Solubility enhancement of poorly soluble drug, nimodipine by modified karaya gum. The aqueous solubility of halofantrine is increased by the addition of caffeine and nicotinamide.

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CONCLUSION: Solubility phenomenon is an area of particular importance. Increasing the water solubility of insoluble or slightly soluble compounds is of major concern for pharmaceutical researchers. A highly solubilized formulation is highly desired to minimize dissolution limited absorption .Often, these early stage formulations become the backbone for the later stage commercial formulations. The aqueous solubility of drug is often a limiting factor in developing most desirable dosage form.

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But still there has been a lot of research going on in this topic and many newer and advanced methods are used to enhance the solubility of the drug.

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REFERENCES: Samuel H. Yalkowsky, Techniques of solubilization of drugs. Encyclopedia of Pharmaceutical technology Vol 3 . Essentials of Physical Pharmacy – subramanyam. Biopharmaceutics and pharmacokinetics -Brahmankar. Enhancement of solubility of valdecoxib by Solid Dispersion Techniques – research paper. Pharmaceutical white papers –solubilization. Martin’s physical pharmacy fifth edition.

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