Solubility Enhancement

Solubility Enhancement Techniques

1. Modern Pharmaceutics Dr. Kailas Mali Professor in Pharmaceutics, Adarsh College of Pharmacy, Vita Solubility Enhancement Techniques

2. Concept of solubility and dissolution. Factors affecting solubility. Factors affecting dissolution. Techniques of solubility / dissolution enhancement. Contents

3. Dissolution It 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. Dissolution is kinetic process, and is quantified by its rate. Rate of dissolution: It is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Introduction Solubility It is a process in which maximum amount of solute dissolved in a given solvent under standard conditions of temp, pressure and pH. Solubility is a characteristic property of a specific solute–solvent combination, and different substances have greatly differing solubilities . Quantifies the dynamic equilibrium state achieved when the rate of dissolution equals the rate of precipitation

4. Process of Solubilisation 1: A single solute molecule is removed from the crystal lattice; energy is required in this step to overcome solute-solute interactions in the solid state. Step 2: A void is created within the solvent to accommodate the solute molecule. Although this step also requires energy, it is likely to be considerably lower than the energy required in step 1. Step 3: The solute molecule inserts into the solvent, forming solute-solvent interactions. Simplistically, if the energy released from the solute-solvent interactions (i.e., step 3) is greater than the energy required for steps 1 and 2, solubility is favored.

5. Forces and Bonds Like dissolves in like. The type of intermolecular forces and bonds vary among each molecule. The chances of solubility between two unlike substances are more challengeable than the like substances. Pressure Gaseous substances are much influenced than solids and liquids by pressure. When the partial pressure of gas increases, the chance of its solubility is also increased. Physical and chemical properties of drug Factors affecting solubility Temperature By changing the temperature we can increase the soluble property of a solute. Generally, water dissolves solutes at 20° C or 100° C. Sparingly soluble solid or liquid substances can be dissolved completely by increasing the temperature. But in the case of gaseous substance, temperature inversely influences solubility i.e. as the temperature increases gases expand and escapes from their solvent .

6. Rate of solution Particle size Temperature Amount of solute dissolved Stirring Factors affecting solubility Nature of solute Nature of solvent Molecular size Polarity Polymorphism pH of solvent pka of drug Rate of solution

7. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. The negative effect of compounds with low solubility include poor absorption and bioavailability, insufficient solubility for IV dosing, development challenges leading to increasing the development cost and time, burden shifted to patient (frequent high-dose administration) Importance of Solubility Therapeutic effectiveness of a drug depends upon bioavailability and ultimately upon the solubility of drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Currently only 8% of new drug candidates have both high solubility and high permeability and nearly 40% of the new chemical entities currently being discovered are poorly water soluble. More than one-third of the drugs listed in the US pharmacopoeia fall into the poorly water soluble category .

8. Factors affecting dissolution Physical characteristics of dosage form. Wettability of dosage unit. Penetration ability of media. The swelling process. The disintegration and deaggregation of dosage form. Dissolution

9. Chemical Modifications Change of pH, use of buffer, derivatization , complexation , and salt formation. Miscellaneous Methods Supercritical fluid process, use of adjuvant like surfactant, solubilizers , cosolvency , hydrotrophy , and novel excipients. Techniques of Solubility Enhancement Physical Modifications Particle size reduction like micronization and nanosuspension . Modification of the crystal habit like polymorphs, amorphous form and cocrystallization . Drug dispersion in carriers like eutectic mixtures, solid dispersions, solid solutions and cryogenic techniques .

10. Techniques of Solubility Enhancement

11. Techniques of Solubility Enhancement Use of Surfactants Surfactants are amphiphilic in nature i.e. composed of hydrophilic as well as lipophilic portions. These molecules have been widely used as solubility enhancers ( solubilizers ). This method is commonly known as micellar solubilization since they form micelles, which are association aggregates of surfactant molecule. Surfactants reduces interfacial tension between solute and solvent. Promotes wetting of particles. Tweens, spans, polyoxyetylene glycerides, polyoxyetylene stearates and Poloxamers .

12. The surfactants like polyoxy ethylene surfactants for ex. Brij 35 or sugar esters like sorbitan monooleate ( Span 80 ), cationic or anionic like alkyltrimethylammonium bromide and sodium dodecyl sulphate or zwitter ionic such as phospholipids like lecithin are used as surfactants to prepare microemulsions . Techniques of Solubility Enhancement Microemulsions A Micro emulsion is an optically clear, isotropic, thermo dynamically stable translucent system which contains a mixture of oil, Hydrophilic surfactant and hydrophilic solvent in which the poorly water soluble drug dissolves . When comes in contact with water the formulation is spontaneously disperse or self emulsified to form a very clear emulsion of exceedingly small as well as uniform oil droplets containing the solubilized poorly soluble drug.

13. The ease of emulsification could be associated with the ease of water penetrating into the various liquids crystalline or gel phases formed on the surface of the droplet. Systems are thermodynamically stable. Large quantity of surfactants irritates GIT. Problem of chemical instability. Techniques of Solubility Enhancement Self- Emulsifying Drug Delivery System A SE or SME system is the concept of in situ formation of emulsion in the GIT. Contains mixture of oil, surfactant, co-surfactant, one or more hydrophilic solvents and co-solvent forms a transparent isotropic solution in the absence of external phase (water ). It forms fine o/w emulsions or micro-emulsions spontaneously upon dilution by the aqueous phase in the GIT and is used for improving lipophillic drug dissolution and absorption.

14. Techniques of Solubility Enhancement pH Adjustment Adjustment of micro-environmental pH to modify the ionization behavior is the simplest and most commonly used method to increase the water solubility behavior. Therfore as per the pH partition hypothesis and Handerson - Hesselbatch equation, ionization of a compound is dependent on the pH of media and pKa of drug. Also the change in the ionic compound can result to in –situ salt formation. Therefore this salt formation is infeasible for unionized compounds. The formed salts may also converse to respective acid or base forms in GIT.

15. Nanoparticle technology is an approach for improving the solubility of drugs that are less soluble in water, namely BCS class II and class IV drugs. The reduction in particle size affects the kinetic solubility of a compound. This is because a reduction in size to <1 mm increases the pressure of the solvation, which increases solubility and also disrupts the interaction of the solute, which facilitates solubilization . Reduction in particle size to <1 μm significantly increases the saturation solubility. Techniques of Solubility Enhancement Particle Size reduction Drug solubility can be increased by reducing particle size, as drug solubility is intrinsically related to drug particle size. If the particle size decreases, the surface area of the drug with a volume ratio increases . A greater surface area allows greater interaction with the solvent , which increases solubility. There are two principal approaches to reducing particle size : micronization and nanonization . Drug particles in the submicron range, referred to as nanoparticles, are <1 μm in size.

16. The thermal stress which may occur during comminution and spray drying is also a concern when processing thermosensitive or unstable active compounds. Using traditional approaches for nearly insoluble drugs may not be able to enhance the solubility up to desired level. Techniques of Solubility Enhancement Conventional methods of particle size reduction, such as comminution and spray drying, rely upon mechanical stress to disaggregate the active compound. Particle size reduction is thus permitting an efficient, reproducible, and economic means of solubility enhancement. However , the mechanical forces inherent to comminution , such as milling and grinding, often impart significant amounts of physical stress upon the drug product which may induce degradation.

17. Ball Milling Ball milling, metal powder is placed in a container with heavy balls. The powder is then processed with high mechanical energy from the balls, which rotate at high speed. There are several types of particle size reduction by milling: low-energy tumbling mill, vibrating ball mill, planetary ball mill, high-energy ball mill, and attrition ball mill . Griseofulvin , progesterone, spironolactone diosmin , and fenofibrate . Techniques of Solubility Enhancement Micronization It is another conventional technique for the particle size reduction. Micronization increases the dissolution rate of drugs through increased surface area, it does not increase equilibrium solubility. Decreasing the particle size of these drugs, which cause increase in surface area, improve their rate of dissolution. Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills and so forth micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug

18. Mechanochemical synthesis Is based on the repetition of welding and deformation from the reactant mixture. The starting material is stoichiometrically mixed and processed by grinding. When grinding, chemical reactions occur on the surface layer between the substrate and the reagent so that the chemical reaction uses only low temperatures . The nanoparticles produced will be dispersed in the salt matrix and subsequently washed using a good solvent and dried at 105°C for 12 h . Techniques of Solubility Enhancement Micronization Advantages The micronization is used to increased surface area for dissolution Micronization increases the dissolution rate of drugs through increased surface area. Disadvantages It does not increase equilibrium solubility Micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug.

19. Tarazepide , atovaquone , amphotericin B, paclitaxel, and buparvaquone . Advantages : 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 Disadvantages : The major concern related to particle size reduction is the eventual conversion of the high-energy polymorph to a low-energy crystalline form, which may not be therapeutically active one. Techniques of Solubility Enhancement Nanosuspension Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug which are stabilized by surfactants. Homogenization and wet milling - Active drug in the presence of surfactant is defragmented by milling. Spraying of a drug solution in a volatile organic solvent into a heated aqueous solution. Rapid solvent evaporation produces drug precipitation in the presence of surfactants . Drying of nanosuspensions can be done by lyophilization or spray drying.

20. Media Milling Using high-shear media mills. The milling chamber charged with milling media, water, drug, and stabilizer is rotated at a very high-shear rate under controlled temperatures for several days (at least 2–7 days). The milling medium is composed of glass, Zirconium oxide, or highly cross-linked polystyrene resin. High energy shear forces are generated as a result of the impaction of the milling media with the drug resulting into breaking of microparticulate drug to nanosized particles. Techniques of Solubility Enhancement Nanosuspension Methods Precipitation drug is dissolved in a solvent, which is then added to antisolvent to precipitate the crystals. It is simple and low cost equipments . The drug needs to be soluble in at least one solvent and this solvent needs to be miscible with antisolvent . Not applicable to drugs, which are simultaneously poorly soluble in aqueous and nonaqueous media.

21. Combined Precipitation and Homogenization The precipitated drug nanoparticles have a tendency to continue crystal growth to the size of microcrystals. They need to be processed with high-energy forces ( homogenisation ). They are in completely amorphous, partially amorphous or completely crystalline forms which create problems in long term stability as well as in bioavailability, so the precipitated particle suspension is subsequently homogenized which preserve the particle size obtained after the precipitation step. Techniques of Solubility Enhancement High Pressure Homogenization The suspension of a drug and surfactant is forced under pressure through a nanosized aperture valve of a high pressure homogenizer. The principle of this method is based on cavitation in the aqueous phase. The cavitations forces within the particles are sufficiently high to convert the drug microparticles into nanoparticles . The concern with this method is the need for small sample particles before loading and the fact that many cycles of homogenization are required.

22. Drug nanocrystal They are composed of 100% drug without carriers and typically stabilized with surfactants or polymeric steric stabilizers. A dispersion of drug nanocrystals in an outer liquid medium and stabilized by surface active agents is so-called nanosuspensions . The dispersion medium can be water , aqueous , or non-aqueous media, e.g. liquid PEG and oils. The nanosuspensions can be used to formulate compounds that are insoluble in both water and oil. Techniques of Solubility Enhancement Nanonization Use of materials and structures at the nanoscale level of approximately 100 nm or less. It is alternate to micronization because micronized product has the tendency to agglomerate , which leads to decrease effective surface area for dissolution. There are different techniques used for nanonization of drug including wet milling, homogenization, emulsification solvent evaporation technique, pear milling, and spray drying.

23. The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from aggregation or growth. Water- redispersible dry powders can be obtained from the nanosized dispersion rather than by conventional methods (e.g., spray drying ). Techniques of Solubility Enhancement Nanomorphs Nanomorph technology converts drug substances with low water solubility from a coarse crystalline state into amorphous nanoparticles to enhance their dissolution. A suspension of drug substance in solvent is fed into a chamber, where it is rapidly mixed with another solvent. Immediately , the drug substance suspension is converted into a true molecular solution. The admixture of an aqueous solution of a polymer induces precipitation of the drug substance.

24. Techniques of Solubility Enhancement

25. Techniques of Solubility Enhancement

26. Polymorphs Polymorphism is the ability of drug moiety to exist in more than one crystalline form. Polymorphs are different crystalline forms of the drug that may have different physicochemical properties and biological activities such as shelf life, melting point, vapor pressure, solubility , morphology , density, bioavailability, and efficacy. Metastable forms are associated with higher energy and increased surface area lead to increase solubility , bioavailability and efficacy. β- polymorph chloramphenicol palmitate . Techniques of Solubility Enhancement C] Modification of the crystal habit Crystal engineering The approach of crystal engineering offers a potentially fruitful method for improvement in solubility, dissolution rate, and finally bioavailability of hydrophobic drugs by polymorphs , Hydrates/solvates method. These techniques are developed for controlled crystallization of drugs to produce high purity powders with well-defined properties as particle size, shape , etc ., leading to stable and robust pharmaceutical products.

27. Controlling the crystallization process , amorphous or meta stable forms of drugs possessing high free energy can be forcibly created. They offer the advantage of higher solubility but suffer from stability issues unless stabilizers intended to inhibit crystal growth are incorporated in the formulation. Techniques of Solubility Enhancement Manipulation of solid state Crystalline to amorphous form. Polymorphism (existence of a drug substance in multiple crystalline forms) can cause variations in melting point, density, stability and drug solubility. Drug that have the highest order of crystallinity is the most stable form, exists in multiple polymorphic forms, i.e. with the least amount of free energy, and , consequently , possesses the highest melting point and the least solubility.

28. When solvent in association with the drug is water, the solvate is known as hydrate and thus have less energy for crystal breakup when compared to anhydrous forms. For example, the antidiabetic drug glibenclamide has been isolated as pentane and toluene solvates which exhibited higher solubility and dissolution rate than the non-solvated polymorphs. Techniques of Solubility Enhancement Hydrates/solvates The stoichiometric type of molecular adducts, in which solvent molecules are incorporated in the crystal lattice of solid is called as solvates. The solvates can exist in different crystalline forms and called as pseudopolymorphs and this phenomenon is called as pseudopolymorphism .

29. Significance It narrows the metastable zone width, Narrows the distribution of particle size, Minimizes the level of cooling process for achieving the crystallization, The process is highly repeatable as well as predictable. Controls the polymorphs . Technology : Ultrasound Mediated Amorphous to Crystalline Transition (UMAX) and Dispersive Crystallization with Ultrasound (DISCUS Techniques of Solubility Enhancement Sono Crystallization It is the process in which the application of ultrasound energy to modify the nucleation of crystallization . The energy of ultrasound leads to compression as well as expansion. After completion of some cycles it forms a bubbles and grows then it collapse. This collapse of formed bubbles gives the energy to enhance the nucleation process which leads to a highly repeatable as well as predictable crystallization process .

30. Solid dispersion Refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or crystalline particles . Therefore , based on their molecular rearrangement , six different types of solid dispersions can be distinguished as a result fine particles formed have shown promising bioavailability of poorly water-soluble drugs. Techniques of Solubility Enhancement Drug dispersion in carriers Eutectic mixtures Eutectic mixtures are formed when the drug and polymer are miscible in their molten state , but on cooling, they crystallize as two distinct components with negligible miscibility. Both drug and carrier exist in the finely divided state, which results in the higher surface area and enhanced the dissolution rate of the drug, for example , sulfathiazole-urea mixture .

31. Hot-melt extrusion method Melt extrusion of miscible components results in amorphous solid solution formation , whereas extrusion of an immiscible component leads to amorphous drug dispersed in the crystalline excipient. Mechanism responsible for solubility enhancement from solid dispersion Reduced Particle Size Drug in amorphous state Particles with high porosity Particles with improved wettability Techniques of Solubility Enhancement Solvent evaporation method Both the drug and the carrier dissolved in a common solvent and then evaporate the solvent under vacuum to produce a solid solution. Advantages : The thermal decomposition of drugs or carriers can be prevented because of the relatively low temperatures required for the evaporation of organic solvents Disadvantages : They are expensive, ecological, and difficult to find common and removable solvents and difficulty of reproducing crystal form.

32. Disadvantages of solid dispersion Instability due to moisture and temperature. Several systems have shown changes in crystalline and a decrease in dissolution rate with aging. Some solid dispersion may not lend them to easy handling because of tackiness. Techniques of Solubility Enhancement Advantages of solid dispersion Results in particles with reduced particle size, and thus, the surface area is increased leads to increase dissolution rate Wettability is improved. Particles in solid dispersions have a higher degree of porosity as a result; solid dispersion particles accelerate the drug release profile which depends on the carrier properties Drugs are presented as supersaturated solutions which are considered to be metastable polymorphic form.

33. According to the extent of miscibility of the two components, solid solutions are the continuous or discontinuous type. In continuous solid solutions , the two components are miscible in the solid state in all proportions. The components that are immiscible at intermediate composition, but miscible at extremes of the composition are referred to as discontinuous solid solutions . Digitoxin , methyl testosterone , prednisolone acetate, and hydrocortisone acetate in the matrix of polyethylene glycol (PEG) 6000. Techniques of Solubility Enhancement Solid solution In amorphous solid solution the drug is molecularly dispersed in the carrier matrix , its effective surface area is significantly higher, and hence , the dissolution rate is increased. The physical stability of amorphous drugs increased due to inhibiting drug crystallization by minimizing molecular mobility. Crystalline solid solution may result when a crystalline drug is trapped within a crystalline polymeric carrier.

34. Techniques of Solubility Enhancement

35. This causes some molecules to minimize the contact with water by aggregation of their hydrocarbon moieties . This aggregation is favored by large planar non-polar regions in the molecule. Stached complexes can be homogeneous or mixed. The former is known as self-association and latter as complexation . Nicotinamide , anthracene , pyrene , methylene blue, benzoic acid, salicylic acid , ferulic acid, gentisic acid, purine, theobromine , caffeine , and naphthalene, etc. form staching complexes. Techniques of Solubility Enhancement Complexation Complexation is the association between two or more molecules to form a non-bonded entity with a well-defined stoichiometry . Complexation relies on relatively weak forces such as London forces, hydrogen bonding, and hydrophobic interactions. Staching complexation Staching complexes are formed by the overlap of the planar regions of aromatic molecules. Non-polar moieties tend to be squeezed out of the water by the strong hydrogen bonding interactions of water.

36. In cyclodextrin inclusion usually only one guest molecule interacts with the cavity of a cyclodextrin molecule to become entrapped and form a stable association. The internal surface of the cavity is hydrophobic and external is hydrophilic; this is due to the arrangement of hydroxyl group within the molecule. Molecules or functional groups of molecules, those are less hydrophilic than water, can be included in the cyclodextrin cavity in the presence of water . Rofecoxib , celecoxib , clofibrate , melarsoprol , taxol , cyclosporine. Techniques of Solubility Enhancement Inclusion complexation Formed by the insertion of the nonpolar molecule or the non-polar region of one molecule (guest ) into the cavity of another molecule or group of molecules (host ). The cavity of the 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 non-polar regions of the host and the guest is reduced. The most commonly used host molecules are cyclodextrins .

37. Co-precipitate method Different molar ratios of active drug are dissolved in ethanol at room temperature, and suitable polymers are mixed, respectively . The mixture is stirred at room temperature for 1 h, and the solvent is evaporated . The resultant mass is pulverized and passed through sieve No. 80 and stored in desiccators . Techniques of Solubility Enhancement Manufacturing techniques Kneading method An active drug with the suitable polymer in different ratios is added to the mortar and triturated with small quantity of ethanol to prepare slurry. Slowly , the drug is incorporated into the slurry with constant trituration . The prepared slurry is then air dried at 25°C for 24 h. The resultant product is pulverized and passed through sieve No. 80 and stored in desiccator over fused calcium chloride.

38. 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. It is considered as an alternative to solvent evaporation method, which involves molecular mixing of drug and carrier in a common solvent. Techniques of Solubility Enhancement Spray drying The solvent evaporation of drug and polymer solution in the different ratio is carried out using spray dryer. The solutions are prepared by dissolving the drug in methanol and polymer in distilled water and mix both solutions, which produces a clear solution. Then solution is spray dried. Lyophilization /freeze-drying technique This is a suitable method to get a porous, amorphous powder with a high degree of interaction between drug and CD.

39. The precipitate so obtained is separated using Whatman filter paper, and dried in vacuum oven at 40°C for 48 h . Techniques of Solubility Enhancement Microwave irradiation method This technique involves irradiation reaction between drug and complexing agent in a microwave oven. The drug and CD in definite molar ratio are dissolved in a mixture of water and organic solvent in a round bottom flask. The mixture is reacted for 1-2 min at 60°C in the oven. After the reaction completes, adequate amount of solvent mixture is added to the above reaction mixture to remove the residual , uncomplexed free drug and CD.

40. Advantages : Increased drug solubility ; increased stability against thermolysis , photolysis , or hydrolysis; good organoleptic properties; and increased tabletability . Disadvantages : Formed salt can transform into its nonionic state from hydrolysis reaction or disproportionation. Disproportionation can change the physicochemical aspect of active drug compounds which result in decreased solubility of drugs. Techniques of Solubility Enhancement Salt formation Salt formation is a neutralization reaction between acids and bases . It is used for drugs that can be ionized so that solubility increases. Salt is formed by the transfer of protons from acids to bases . Acidic and basic drugs are converted into respective salt forms, e.g., aspirin , theophylline , and barbiturates. Alkali metal salts of acidic drugs such as penicillins and strong acid salts of basic drugs such as atropine are water soluble than parent drugs.

41. When salt is formed, the components in the crystal lattice are in an ionized state, the cocrystal component is in a neutral state, and it interacts through nonionic interactions. Cocrystals consist of API with a neutral guest compound termed cocrystallization formers ( coformers ) in the same crystal lattice. Coformers : Citric acid , glutamic acid, gallic acid, ascorbic acid, histidine, glycine , nicotinamide , valine , tyrosine, urea, and saccharine) and nutraceuticals (e.g., p- coumaric acid, quercetin , pterostilbene , and saccharine. Techniques of Solubility Enhancement Co-crystallization It is a molecular complexation process to form co-crystals. A co-crystal may be defined as crystalline material that consists of two or more molecular species with a stoichiometric ratio at room temperature held together by non-covalent bonds usually hydrogen bonds. Cocrystallization produces new crystalline shapes that are often superior to each separate component . Cocrystals have increased drug solubility because of the lower lattice energy and higher affinity of the solvent .

42. Advantages It is an alternative to salt formation, particularly for neutral compounds . Cocrystallization has the potential to be applied to API under acidic , basic, and nonionized molecules. Storage age of the API can be extended by using cocrystals in pharmaceutical products. Disadvantage Cocrystal formation is not guaranteed. Fluoxetine hydrochloride formed cocrystals with succinic acid. Techniques of Solubility Enhancement Co-crystallization Methods S olution evaporation, solid-state co-grinding ( without or with solvent), co-melting, co-sublimation, and co-heating. Sophisticated techniques: Cocrystallization by extrusion ; sonococrystallization ; cocrystallization from suspensions ; electrochemically induced cocrystallization ; cocrystallization from supercritical fluids; cocrystallization by laser irradiation ; freeze-drying cocrystallization ; spray drying cocrystallization ; and cocrystallization from polymers, ionization, and polymer gels.

43. Advantages Increase solubility is a low risk of failure of formulation, and it does not require complicated formulation equipment. Disadvantages Tolerability and toxicity due to the use of nonphysiological pH. Drugs in formulations with pH adjustment can become difficult to dissolve and settle when diluting in aqueous media or can cause embolism if given intravenously . The drug is also less stable under water conditions , as hydrolysis or other degradation can increase Techniques of Solubility Enhancement pH adjustment By this method, the hydrophobic molecule can be protonated ( base) or deprotonated (acid) and be dissolved in water by applying a pH change. Ionizable compounds that are stable and soluble after pH adjustment are best suited . The poorly water-soluble repaglinide is formulated with meglumine as a pH modifier. Most intravenous formulations contain lactic acid as a pH modifier to increase solubility. Aspirin effervescent tablets.

44. Cosolvents Techniques of Solubility Enhancement Co-solvency Cosolvents are mixtures of water and/or more water miscible solvent used to create a solution with enhanced solubility for poorly soluble compounds, e.g., PEG 300, propylene glycol, or ethanol, PVA, PVP, Poloxamer 407, etc. Dimethyl sulfoxide and dimethylacetamide have been widely used as cosolvent because of their large solubilization capacity of poorly soluble drugs and their relatively low toxicity. Simple and rapid to formulate and produce. Excipients toxicity and tolerability.

45. Advantages Better than miscibility , micellar solubilization , cosolvency , and salting in, because the solvent character is independent of pH. Has high selectivity and does not require emulsification or organic solvents or chemical modification. It only requires mixing the drug with the hydrotrope in water. Disadvantage Gather alone in solution. Eg : Ketoprofen , aceclofenac , salicylic acid, cefixime , tinidazole , frusemide , and amoxicillin Techniques of Solubility Enhancement Hydrotrophy Increase in the aqueous solubility of BCS Class II drugs by the addition of alkali metal salts of various organic acids. Improves solubility by complexation involving a weak interaction between drug an the hydrotropic agents. Hydrotropes are organic amphiphilic molecules ( sodium benzoate, sodium salicylate, urea, nicotinamide , sodium citrate and sodium acetate) with similar structural features to surfactants. In hydrotropic drug solubilization the hydrotrope concentrates the drug molecules.

46. Also acceptable solution stability to provide an appropriate product shelf life and the ability to rapidly convert to the pharmacologically active parent drug. In addition, the promoieties must also prove to be nontoxic. Water soluble prodrugs of steroids such as sodium hemisuccinate esters and sodium phosphate esters represent the successful examples for the use of prodrugs of poorly soluble drugs for intravenous (IV) administration. Techniques of Solubility Enhancement Prodrug A prodrug is a drug molecule which is a covalently bound to a pharmacologically inactive moiety also known as promoiety with the aim to overcome on the various physicochemical and biopharmaceutical limitations of the parent drug. It is an key objective when applying into a class II or IV poorly soluble drug with respect to solubility enhancement. Perticullarly , a prodrug should possess an adequate solubility to be formulated into a solution for IV administration.

47. When supercritical CO 2 is used as solvent, matrix and drug are dissolved and sprayed through a nozzle, into an expansion vessel with lower pressure and particles are immediately formed. Create nanoparticulate suspensions of particles 5–2,000nm in diameter . Methods: Precipitation with compressed antisolvent process (PCA), solution enhanced dispersion by SCF (SEDS), supercritical antisolvent processes ( SAS), rapid expansion of supercritical solutions (RESS), gas anti solvent recrystallization (GAS), and aerosol supercritical extraction system (ASES) Techniques of Solubility Enhancement Supercritical Fluid Technique Supercritical fluids are fluids whose temperature and pressure are greater than its critical temperature ( Tc ) and critical pressure ( Tp ), allowing it to assume the properties of both a liquid and a gas . At near-critical temperatures, SCFs, are highly compressible allowing moderate changes in pressure to greatly alter the density and mass transport characteristics of the fluid that largely determine its solvent power. SCF methods are mostly applied with CO 2 , which is used either as a solvent for drug and matrix or as an antisolvent .

48. Spray Freezing onto Cryogenic Fluids Spray Freezing into Cryogenic Liquids Spray Freezing into Vapor over Liquid Ultra-Rapid Freezing Techniques of Solubility Enhancement Cryogenic Techniques Creates 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). Dry powder can be obtained by various drying processes like spray freeze drying, atmospheric freeze drying , vacuum freeze drying, and lyophilisation .

49. Thank you Professor in Pharmaceutics, Adarsh College of Pharmacy, Vita, Sangli 415311 [email protected] [phone]