P.formulations solutions

Pharmaceutical Formulations - Solutions

1. SOLUTIONS By ANAND A Assistant Professor Shri Vishnu College of Pharamcy

2. Definition A solution is a HOMOGENEOUS mixture of 2 or more substances mixed evenly at molecular level. One part is regarded as the SOLUTE and the others as SOLVENT. Parts of a Solution Solute-the part that gets dissolved Solvent-the part that does the dissolving

3. SOLUTE –material being dissolved (usually the lesser amount) SOLVENT – material doing the dissolving (usually the greater amount) Solute + Solvent =Solution

4. 1. Solution Definitions Soluble - capable of being dissolved. 2. Solution – homogeneous mixtures 3. Saturated – exactly the right amount of dissolved solute for a particular solvent 4. Unsaturated –less solute than can be dissolved by a solvent to be saturated 5. Supersaturated -more dissolved solute than saturated. Has to be specially made; unstable

5. Formulation Considerations Many Technical problems - Solubility Drug is unstable Special Techniques are required to solubilise Preparation should satisfy pharmaceutical elegant –Taste, appearance and Viscosity

6. Factors for consideration of Solubility pH Cosolvency Dielectric Constant Solubilization – by addition surfactants (CMC) Complexation Hydrotrophy Chemical Modification of the drug.

7. Factors influencing solubility of a drug pH Cosolvency Dielectric constant Solubilization Complexation Hydrotrophy Chemical modification of drug

8. Solubility Solute dissolves in given system and the extent to which it dissolves depends largely on the nature and intensity of the forces present in the solute, solvent and solute-solvent interaction. Determination of Equilibrium solubility – Excess amount of drug taken in a vial consisting of solvent agitated for a period of time and drug conc. Is determined after filtering sample solution. Equilibrium is achieved when two successive sample give same reading. Solubility studies are conducted at constant Temperature 30 C.

9. pH: Drugs are either weak Acids or weak Bases. The solubility of these are influenced by pH of the environment. DH(Solid) DH(Solution) Where DH(Solution) is equal to the solubility of undissociated acid in moles per liter and is a constant generally referred to as Ks . S T =[DH]+[D - ] Undissociated acid Is also equilibrium with its dissociation product. or Equation is useful for determining total solubility of WA at a pH

10. Selection of Buffer: Buffer must be adequate capacity in the desired pH range. Biologically safe for the intended use. Little or no deleterious effect on the stability of the final product. Permit acceptable flavouring and colouring of the product. In general, a buffer system has adequate capacity within one pH unit of pK.

11. Cosolvency : Weak electrolytes and nonpolar molecules are poor water solubility. Cosolvency – Addition of water miscible solvent to increase the poorly soluble drug. Cosolvent – solvents used in combinations to increase solubility of drug. It has proposed that a cosolvent system works by decreasing the interfacial tension between aq. Soln and hydrophobic solute. Eg : Ethanol, sorbitol, glycerin, Propylene glycol, PEG’s Dimethyl acetamide used as a cosolvent in parenteral products, but it should not be used in orally due to its objectionable odour and taste which will be difficult to mask.

12. Cosolvents are also used to improve the solubility of volatile constituents which are used to impart flavor to the product. Hildebrand and Scott developed equation that yield thermodynamic measure of cohesive forces that exists with in the homogeneous substance. Hildebrand’s solubility parameter

13. Dielectric constant: Every solute shows a maximum solubililty , in any given solvent system, at one or more specific dielectric constants. The absolute solubility of a solute may vary considerably in two different solvents of the same dielectric constant, but the solubility profile as a function of dielectric constant appears to be similar for a solute in a wide variety of solvent system. To determine the dielectric requirement of the substance of interest, dioxane -water blends having known dielectric constant are used, and the dielectric constant at which maximum solubility is attained is noted.

14. Solubilization : Using Surfactants (CMC) The spontaneous passage of poorly water soluble solute molecules into an aqueous solution of soap or a detergent, in which a thermodynamically stable solution is formed. Mechanism – formation of Colloidal aggregates - micelles

15. Solubilization occurs by virtue of solute dissolving in or being adsorbed onto the micelle. Thus the ability of surfactant solution to dissolve or solubilize insoluble drug start at CMC and increase with concentration of micelles. Any material can be solubilized in any solvent by proper choice of solubilizing agent. Lyophilic surfactants with HLB >15 are best solubilizing agent. Final selection of solubilizing agent is based on phase solubility studies. Addition of Surfactant to drug system some times enhances the Gi -absorption and pharmacologic activity and some other cases inhibited the same.

16. Commonly used nonionic surfactants include polysorbates , polyoxyethylated castor oil, polyoxyethylated glycerides, lauroyl macroglycerides , and mono- and di-fatty acid esters of low molecular weight polyethylene glycols. Surfactants are also often used to stabilize microemulsions and suspensions into which drugs are dissolved. Examples of poorly soluble compounds that useMicellar solubilization are antidiabetic drugs, gliclazide , glyburide, glimepiride , glipizide, repaglinide, pioglitazone, and rosiglitazone.

17. Complexation: Association of organic molecules occurs commonly in solutions, this association is too weak to detect by std tech. Intermolecular association can be readily observed by Solubility analysis technique. Every substance has a specific, reproducible equilibrium solubility in a given solvent at a temp. Any deviation from this inherent solubility must be due to formation of a new species in solution. In case of weakly acidic or basic drug total solubility is equal to the inherent solubility of dissociated compound plus conc. of dissociated species. S T =[DH]+[D - ]

18. Similarly when complexation occur the total solubility is equal to inherent solubility of uncomplexed drug plus the conc. Of drug complex in solution.

19. Hydrotrophy : Hydrotropic effect, the meaning is taken as the increase in saturation solubility of a substance in water by the addition of organic salts or also non-electrolytes, which of course must be physiologically compatible for pharmaceutical application. The mode of action of the hydrotropic substances is thought to be due to either an associate formation , in low concentrations to a formation of molecular complexes or in higher concentrations to the water structure being influenced. These hydrotropic substances are able to increase the number of hydrogen bridges in the water clusters. This makes the water more hydrophobic & thus it is a better solvent for non-polar drug However , the use of hydrotropic substances such as sodium benzoate, nicotinamide, urea , caffeine, sorbitol, etc.

20. Hydrotropy is a solubilization phenomenon whereby addition of large amounts of a second solute results in an increase in the aqueous solubility of another solute . Hydrotropes are a class of amphiphilic molecules that cannot form well organized structures, such as micelles, in water but do increase the aqueous solubility of organic molecules. Strong synergistic effects are observed when hydrotropes are added to aqueous surfactant or polymer solutions. A hydrotrope is a compound that solubilises hydrophobic compounds in aqueous solutions. Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part (like surfactants) but the hydrophobic part is generally too small to cause spontaneous self aggregation .

21. Hydrotropes do not have a critical concentration above which self-aggregation 'suddenly' starts to occur (as found for micelle- and vesicle-forming surfactants, which have a critical micelle concentration or CMC and a critical vesicle concentration, respectively Instead, some hydrotropes aggregate in a step-wise self-aggregation process, gradually increasing aggregation size. However, many hydrotropes do not seem to self-aggregate at all, unless a solubilisate has been added . Lage conc. Of sodium benzoate is used to solubilize caffeine and benzoic acid and theophylline with sodium acetate and sodium glycinate .

22. Chemical Modification of drug Poorly soluble drugs are chemically modified in water soluble derivatives Eg : corticosteroids. This approach has several limitations as a parent compound like biological activity studies, acute and chronic toxicity, pharmaceutical evaluation and clinical testing.

23. Manufacturing Consideration: Raw materials Equipment Compounding Procedure Packaging A homogeneous product – solubility of solute and intra and inter molecular interaction in final solution at equilibrium are independent.

24. Raw materials: Sweetening agents Viscosity controlling agents Flavours Colouring agents – Appearance ( Colour & Clarity) Preservatives Purified Water USP.

25. Sweetening agents: For improving or Masking taste of drug. Sucrose at high conc 85% Others are sorbitol, glycerin and polyols (Glycerol, PEG,PG)– Reduce tendency of sucrose to crystallize. Sucrose crystallize at threads of bottle cap and interfere with cap removal – Can be minimized by using above ones with sucrose. Liquid glucose – partial hydrolysis of starch with strong acid It contain dextrose and small qty of dextrins and maltose Some synthetic sweetners Saccharin – 250-500 times, bitter after taste. Aspartame – 200 times, it is a methyl ester of aspartic acid, and phenylalanine. Its taste is improved with sodium bicarbonate gluconate salts and lactose.

26. Viscosity Control It is desirable for palatability and or improve pourability . Achieved by increasing sugar conc. Or incorporating viscosity controlling agents. Eg : PVP or cellulose derivatives(MC or CMC). CMC ppt in solutions containg multivalent metal ions(Al 3+ ,Fe 3+ , Ca 2+ ) These form organic molecular complexes with organic or inorganic compounds High viscid systems resist dilution with GI-fluids might impede drug release and absorption.

27. Flavours : Four basic sensations Salty, Bittter , Sweet and sour. A combination of FA required to mask taste sensation effectively. Menthol and Chloroform are desensitizing agents. Monosodium glutamate in Food industry Selection depends on trial and error basis in diluted samples To Flavored vehicle add increments of medicament to check The conc at which the taste of the medicament is perceptible is referred to as the “min threshold level”

28. Appearance: Overall appearance depends on colour and clarity. Colour selection depends on flavor eg : green or blue for mint, red for berry. Dyes are majorly used. Clarity – particulate matter from through lint or fibers from solvent or insoluble contaminants from components. Ppt of pectin in alcoholic and resin in aqueous soln Removal of these particulate material is known as “ Polishing” It can be done by Settling and subsequent decantation By centrifugation By filtration

29. Filtration by using Filter pads used for oral liquids Made of asbestos or asbestos with cellulose. Now a days membrane filters are used due to asbestos fiber` contamination in product which causing cancer.

30. Preservation: Microbiologial safe for oral or topical liquid. Source of contaminations Rawmaterials Processing containers and equipment Mfg environment Operators Packaging material user

31. Ideal preservative should qualitatively meet: It must be effective against broad spectrum of MO. Physically, Chemically and Microbiologically stable. Nontoxic, nonsensitizing , soluble, compatible and acceptable wrt taste and odour at the conc. Usually a combination of preservative are used

32. Phenols are less used due to its odour and stability. Methyl and propyl parahydroxy benzoic acid are widely used Neutral preservatives are volatile alcohols - odour problem – loss of conc on ageing. Mecurials and quaternary ammonium compounds are highly incompatible with anionic drugs. Syrup of sucrose >85% conc. Resists bacterial growth by exosmotic effect on MO’s. Surface dilution takes place in closed container – chance to grow MO’s Alcohol of 5-10% can minimize problem

33. WATER: Most important constituent in liquid preparation. Meet USP requirement of purified water. Obtained by distillation of ion-exchange process. Reverse osmosis purification, ultraviolet sterilization and membrane filtration. Ambergard XE-352 – large pore, macroreticular Type I quaternary ammonium anionic resin. Amberlite IR -120 – Strongly acidic cation exchange resin.

34. Equipment Mixing tank – agitation – stainless steal – steam jacketed Measuring devices Filtration system – for polishing and or/ Sterilization Piping , valves, mixers, pumps and controls All equipment cleaned and sanitized before use. Dil. Soln of H2O2 or phenol derivatives and peracetic acid Sterilization by alcohol, boiling water, autoclaving-steam or dry heat.

35. Compounding procedure

36. Packaging: Filling of liquid depends on characteristic of liquid – Viscosity, surface tension, foam quality and compatibility. 3 filling methods – Gravimetric, volumetric and constant level Gravimetric – Filling containers to given weight is limited to large containers or Highly viscous products. Process can not lend itself to high speed , automatic equipment. Volumetric – accomplised by positive displacement piston action. fill amount is measured by stroke of the piston. Problems: - viscous liquids can not be filled- piston to seize – loss of fill accuracy or line breakdown, thin liquids flow past the piston results fill inaccuracy. Selection of containers should be in dimensionally uniform oversized package appears – slack fill undersized package appears- excessive fill

37. Constant level – it involves the use of siphon, usually slow proces For high speed – induced pressure differential b/w liquid discharge nozzle and constant level overflow system. Vacuum filling Gravity – vacuum filling Pressure-vacuum filling Problems in filling is – foaming , Can be minimized by – equipment that minimize turbulence, closed system limits the entry of air or gases, defoaming devices, reduction in the speed of filling line