SOLUBILIZATION TECHNIQUES -

SOLUBILIZATION TECHNIQUES: 

SOLUBILIZATION TECHNIQUES Karan Mistry M.Pharm Pharm tech.,IICP 1

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SOLUBILIZATION TECHNIQUES Hydrotropic Solubilization Micellar S olubilization Solid Dispersion Solid Solution Fast Dissolving Dosage Forms 2

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1. Hydrotropic solubilization Hydrotropic agent are ionic organic salts which, at high concentrations, considerably increase the aqueous solubility of poorly soluble solutes. Hydrotropy is a solubilization phenomenon whereby addition of large amount of second solute results in an increase in the aqueous solubility of another solute. Additives or salts that increase solubility in given solvent are said to “ salt in ” the solute and those salts that decrease solubility "salt out” the solute. Some salts with large anions or cations that are themselves very soluble in water result in “salting in” of non electrolytes called “hydrotropic salts” a phenomenon known as “hydrotropism”. 3

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Examples, sodium benzoate, nicotianamide, urea, caffeine, sorbitol, etc . Advantages of hydrotropic solubilization technique Hydrotropy is suggested to be superior to other solubilization method, such as miscibility, micellar solubilization, co solvency and, because the solvent character is independent of pH, has high selectivity and does not require emulsification. It only requires mixing the drug with the hydro trope in water. 4

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Mixed hydrotropy Mixed hydrotropic solubilization technique is the phenomenon to increase the solubility of poorly water-soluble drugs in the blends of hydrotropic agents, which may give miraculous synergistic enhancement effect on solubility of poorly water soluble drugs. By the use of this we can reduce concentration of individual hydrotropic agent to minimize the side effects. Disadvantages of hydrotropic solubilization technique Slight increase in solubility with high concentration of hydrotropic agents, that sometime leads to toxicity. 5

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2. Micellar solubilization SURFACTANTS polar (hydrophilic) head non–polar (hydrophobic) tail which at low concentrations, adsorb onto the surfaces or interfaces of a system & alter the surface or interfacial free energy & decrease interfacial tension. Examples, Anionic surfactant: SLS, Potassium laurate . Cationic surfactant: Cetrimide. Amphoteric surfactant: N- dimethylbetaine . Non ionic surfactant: Spans & Tweens . 6

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Micelles : in the water, as the concentration of surfactant increases above a critical value, its molecule self associate into structures called micelles and the concentration at which they begin to form is called Critical Micelle Concentration . 7

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Miceller solubilization can be defined as the spontaneous dissolving of a substance by reversible interaction with the micelles of a surfactant in water to form a thermodynamically stable isotropic solution. Schematic plot of the concentration of a poorly soluble compound as a function of the surfactant concentration in aqueous solution 8

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Possible location of solubilization of drugs in surfactant micelles hydrophilic drugs can be adsorbed on the surface of the micelle. drugs with intermediate solubility should be located in intermediate positions within the micelle such as between the hydrophilic head groups of PEO micelles in the palisade layer between the hydrophilic groups and the first few carbon atoms of the hydrophobic group, that is the outer core. completely insoluble hydrophobic drugs may be located in the inner core of the micelle 9

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Factors that affect solubilization Temperature The ionic strength pH Disadvantages of this technique Extent of solubilizing effect is too low. Bad stability due to incompatibility between surfactants & drug. Change in bioavailability. Frequently too high surfactant concentration are necessary. 10

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3. Solid Dispersion It is defined as “a dispersion of one or more ingredients in an inert carrier or matrix in solid state prepared by the melting (fusion) method, solvent method or melting-solvent method ”. Dispersions obtained through the fusion process are often called as melts, and those obtained by solvent method are called as co precipitates or co evaporates . 1. To improve drug solubility. 2. To improve drug stability. 3. To mask the bitter taste of drug. 4. To dispense liquid or gaseous compounds. 5. To obtain required release profile Solid dispersions are prepared to: 11

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Classification of Solid Dispersion Simple eutectic mixture. Solid solution. Glass solution and glass suspension. Amorphous precipitations in a crystalline carrier. Combinations of previous types Example, A solid dispersion of carbamazepine in polyethylene glycol 4000 (PEG-4000) increased the rate and extent of dissolution of carbamazepine. 12

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1. Simple eutectic mixture A simple eutectic mixture consists of two compounds which are completely miscible in the liquid state but only to a very limited extent in the solid state. It is prepared by rapid solidification of fused melt of two components that show complete liquid miscibility but negligible solid-solid solution. Phase diagram for a eutectic system 13

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2. Glass solution and glass suspension A glass solution is a homogenous system in which a solute is dissolved in glass carrier. A glass suspension refers to a mixture in which precipitated particles are suspended in glassy solvent. 14

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3. Amorphous precipitations in a crystalline carrier Instead of forming simple eutectic mixture in which both drug and carrier crystallize simultaneously, the drug may also be precipitated out in amorphous form in a crystalline carrier. Since the amorphous form is the highest energy form of the pure drug, it produce faster dissolution and absorption rates than the crystalline form. It is postulated that a drug with high supercooling property has more tendency to solidify as an amorphous in the presence of a carrier. 15

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4. Combination of different types Quite often a solid dispersion does not entirely belong to any of the groups discussed previously, but is made up of combination of different groups. Therefore, observed increase in dissolution and absorption rate may be the combination of different mechanisms . e.g. Sulfathiazole dispersed at high concentration in PVP may exist as - individual molecule - sulfathiazole- pvp complex molecule - amorphous and polymorphic molecule - amorphous sulfsthiazole-pvp complex 16

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Methods of Preparation of Solid Dispersion Melting / fusion method. Co-precipitation method SCF Dropping method Hot stage extrusion Hot stage extrusion method Hot stage extrusion has in recent years gained wide acceptance as a method of choice for the preparation of solid dispersions. The hot stage extrusion process is highly dependent on the physicochemical properties of the compounds and their miscibility in the molten state. 17

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Hot stage extrusion consists of the extrusion, at high rotational speed, of the drug and carrier, previously mixed, at melting temperature for a small period of time. Extrusion then collected after cooling at room temperature and milled. Advantages of Solid Dispersion Improving drug bioavailability by changing their water solubility has been possible by solid dispersion. Solid dispersions are more efficient than these particle size reduction techniques, since the latter have a particle size reduction limit around 2–5 mm which frequently is not enough to improve considerably the drug solubility or drug release in the small intestine. 18

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Transformation of liquid form of drug into solid form. Parameters, such as carrier molecular weight and composition, drug crystalline and particle porosity and wettability, when successfully controlled, can produce improvements in bioavailability Disadvantages of Solid Dispersion most of the polymers used in solid dispersions can absorb moisture, which may result in phase separation, crystal growth or conversion from the amorphous to the crystalline state or from a metastable crystalline form to a more stable structure during storage. This may result in decreased solubility and dissolution rate. 19

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4. Solid Solution “A solid solution is a binary system comprising of a solid solute molecularly dispersed in a solid solvent. Since the two components crystallize together in a homogenous one phase system, solid solutions are also called as molecular dispersions or mixed crystals OR Melts”. Melts and co precipitates are solid dispersion that provide a means for reducing particle size to a molecular level. so solid solutions show greater aqueous solubility and faster dissolution than eutectics and solid dispersions. The use of dispersion method to obtain physically modified form of a drug which are much more rapidly soluble than pure compound. 20

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Composition of the solid solution Poorly water soluble drug Carrier (polymer or polymer blends ) Solvent (to dissolve the phase if necessary ,depends on the methodology used) Additives (co solvents or glycerol) Recrystallization inhibitors Solid solution can be classified by two ways: Based on miscibility Based on molecular size Continuous solid solution Discontinuous solid solution Substitutional solid solution Interstitial solid solution 21

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Melting Method for preparation of solid solution The physical mixture of a drug and a water-soluble carrier was heated directly until it melted, The melted mixture was then cooled and solidified rapidly in an ice bath under rigorous stirring . The final solid mass was crushed, pulverized, and sieved. To facilitate faster solidification, the homogeneous melt was poured in the form of a thin layer onto a ferrite plate or a stainless steel plate and cooled by flowing air or water on the opposite side of the plate. The solidified masses of drug-polymer systems were often found to require storage of 1 or more days in a desiccators at ambient temperatures for hardening and ease of powdering. 22

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Advantages of Solid Solution Improving drug bioavailability by changing their water solubility has been possible by solid solutions. Disadvantage of Solid Solutions Thermodynamically unstable systems . Drug capable of degradation but also the carrier material can undergo chemical stability problems. 23

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5. Fast Dissolving Dosage Forms A fast-dissolving drug delivery system, in most cases, is a tablet that dissolves or disintegrates in the oral cavity without the need for water or chewing. A dosage form for the oral administration which when placed in mouth, disintegrates rapidly or dissolves & can be swallowed in the form of liquids. 24

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Conventional techniques used for the preparation of the fast dissolving products Tablet moulding Spray drying Lyophilization Sublimation Addition of disintegrants (super-disintegrants & effervescent disintegrants) Patented technologies of fast dissolving products Zydis , Orasolv , Durasolv , Flashtab 25

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Advantages of FDDTs Improved compliance/added convenience Ease of administration Requires no water intake Quick disintegration & dissolution of dosage form Can be designed to leave minimal or no residue in mouth after administration & also provide a pleasant mouth feel Allows high drug loading 26

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REFERENCES : International Journal of Drug Development & Research, “ HYDROTROPY: A PROMISING TOOL FOR SOLUBILITY ENHANCEMENT: A REVIEW”, April-June 2011,Vol. 3, pg.27-33 International Journal of Pharmaceutical Sciences Review and Research, Volume 8, Issue 2, May – June 2011, pg.66-72 Journal of Pharmaceutical sciences, Sep-1971, Vol 60, pg.1283-1290 Encyclopedia of Pharmaceutical Technology, Vol.18, Pg.161-212 27