Liquid Dr. Asmaa Abdelaziz Mohamed PH.D of Pharmaceutics
Formulation Considerations • Solubility • Preservation • Subjective product characteristics • sweeting agents: • Flavors • appearance
Approaches for improvement of aqueous solubility: 1-pH control. 2-cosolvency 3-solubilization 4-complexation 5-chemical modification 6-particle size
1- pH • Either drug is weak acids or weak bases. Its solubility can be influenced by the pH of their environment. • the solubility of weak base can be increased by lowering of pH while solubility of weak acid is increased by increasing pH • In controlling solubility of the drug we must assure that pH does not conflict with other requirements. • pH of solutions for parenteral and ophthalmic use must be controlled as extremes can cause pain and irritation • In some instances the bioavailability of drug & preservative activity may be influenced by pH • The maximum solubility must be achieved by a balance between pH and conc. of cosolvent.
Cont. pH -In selecting pH for adequate solubility several factors should be considered such as stability. The criteria for selecting buffer: 1-The buffer must have adequate capacity in the desired pH range 2-The buffer must be biologically safe 3-The buffer should have little or no damage effect on stability 4-Buffer should permit acceptable flavoring and coloring of product -The solubility of non electrolyte is not affected by hydrogen ion concentration so solution is achieved by cosolvents, solubilisation, complexes or chemical modification of the drug to more soluble derivative
2- Cosolvency • increasing solubility of weak electrolyte or non polar compounds in water can be achieved by addition of water miscible solvent (cosolvent) in which the drug has good solubility. • Mechanism of cosolvency by reducing interfacial tension between aqueous solution and the hydrophobic drug. • Cosolvents such as ethanol, sorbitol, glycerin and propylene glycol. • ideally suitable blends should posses value of dielectric constant between 25 and 80 the most widely systems that covers this range are water/ethanol blend or sorbitol, glycerol, propylene glycol and syrup
3-Solubilization • Solubilization is defined as 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. • The mechanism involves surface-active agents known as micelles. • When surfactants are added to a liquid at low concentration, they tend to orient at the air-liquid interface. As additional surfactant is added, the interface becomes fully occupied, and the excess molecules are forced into the bulk of the liquid. • At still higher conc., molecules of surfactant in liquid begin to form micelles; this change in orientation occurs suddenly, and conc. of surfactant at which it occurs is known as the critical micelle concentration (CMC). • the ability of surfactant solutions to solubilize water-insoluble materials starts at the critical micelle concentration and increases with the conc. of the micelles.
4-Complexation • In some cases, it may be possible to interact a poorly soluble drug with soluble material to form intermolecular complex however these complexes may be inactive so it is important that these complex to be easily reversible so the free drug is released during or before contact with biological fluids • The term hydrotropy is defined as the increase in aquous solubility of a material by inclusion of additives. • Ex inclusion of iodine with povidone to improve solubility of iodine
5-Chemical modification : may be necessary to produce water soluble derivative Ex. Synthesis of sodium phosphate salts of prednisolone and hydrocortisone 6-Particle size control: as particle decrease solubility will increase b) Preservation: there are numerous sources of contamination including raw materials, equipment , personnel, packaging material Criteria for Ideal preseravative : 1-Effective against broad spectrum of microorganisms1- 2-Physically, chemically and microbiologically stable 3-throughout shelf life 4-Non toxic c) subjective product characteristics:the product should be elegant
d) sweeting agents: sucrose: most syrup contains 60-80 sucrose liquid glucose: is prepared by hydrolysis of starch with strong acid contains its main content dextrose with smaller amounts of dextrin and maltose saccharin: 250-500 times sweet as sugar. Its disadvantage bitter aftertaste aspartame: 200 times sweet as sucrose. e)flavors: the four basic taste sensations are salty, bitter, sweet and sour. selection: f)Appearance: To enhance the appeal of the liquid, a coloring agent is generally used which correlates with the flavorant employed. For example, mint-flavoured formulations are commonly a green colour, whereas in banana-flavoured solutions a yellow colour is commonly employed. The colorant used is generally water-soluble, non-reactive with other components, and color stable at the pH range and under the intensity of light that the syrup is likely to encounter during its shelf life.
Stability Studies: chemical and physical stability of solution studies are done in their intended container Chemical Stability May be done by accelerated stability testing or making long term stability testing Physical Stability A physically stable oral liquid retains its viscosity, color, clarity, taste, and odor throughout its shelf-life. Color can readily be measured UV spectrophotometrically & compared with the initial value to determine the extent of color change. Clarity is best determined by shining a focused beam of light through the solution. Taste and odor. The odor and taste of the reference sample should be known to be intact. Product stored in the refrigerator frequently is used as the reference sample. Most oral liquids are packaged in either amber or flint glass containers with plastic or metal caps. Fortunately, glass is generally inert to aqueous solutions in the pH range appropriate for oral liquids. The same is not necessarily true for the cap and liner. Plastic caps may undergo stress cracking on contact with some liquids, whereas under same conditions, corrosion may be a problem with metal caps. In both cases, it is important to select a liner that on the basis of actual testing, is compatible with the package contents
Equipment • mixing tanks equipped with a means of agitation, measuring devices for large and small amounts of solids and liquids, and a filtration system for the final polishing and/or sterilization of the solution. • All equipment must be cleaned and sanitized (sterilized if possible) • before use. • Appropriate disinfectants include dilute solutions of hydrogen peroxide, phenol derivatives, and peracetic acid. • Equipment and lines can be sterilized by such methods as alcohol, boiling water, autoclaving, steam, or dry heat. • Tanks are usually constructed of polished stainless steel and are usually jacketed to allow for heating or cooling of the contents. • A major source of microbial contamination is often the processing • operators. Head covering should be worn at all times, Gloves and face • masks should be worn as necessary.
Suspensions • Suspensions may be defined as preparations containing finely divided drug particles distributed throughout water in which the drug exhibits a minimum solubility”
Some suspensions are available in ready-to-use form, that is, already suspended in a liquid. • Other preparations are available as dry powders to be suspended in liquid (reconstitution powders). Drugs that are unstable in the presence of water (e.g., antibiotics) are frequently supplied as dry powder for reconstitution. Reasons for Suspension Preparation • For example, certain drugs are chemically unstable in solution but stable when suspended. For example, oxytetracyclineHCl is used in solid dosage forms, but it rapidly decomposes in aqueous solution. • A stable liquid dosage form has been made by suspending the insoluble calcium salt in a suitable aqueous vehicle. • For many patients, the liquid is preferred to the solid form of the same drug because of the ease of swallowing. • The disadvantage of unpleasant taste of certain drugs in solution form is avoided when the drug is administered as undissolved particles in a suspension. Ex:erythromycinestolate is a less water-soluble prodrug of erythromycin and is used to prepare a palatable liquid dosage form of erythromycin.
Desirable Features of Suspensions: • A properly prepared suspension should settle slowly and remain homogenous for at least the period between shaking the container and removing the required dose. 2. The sediment produced on storage should be readily redispersed upon gentle shaking of the container. 3. The particle size of the suspended drug should remain constant throughout long periods and do not show crystal growth (i.e., physically stable). 4. The suspension viscosity must not be very high and it should be poured easily from its container
Cont.The Sedimentation Rate • One of the most rapid, convenient, and inexpensive methods of producing fine drug powders of about 10-50 µm is micropulverization. • Micropulverizers are high-speed mills that are efficient in reducing powders to the size acceptable for most suspensions. • For finer particles, under 10 µm, jet milling (also called micronization), is quite effective. • Although the particle size of a drug may be small when the suspension is first manufactured, there is always a degree of crystal growth that occurs on storage, particularly if temperature fluctuations occur. This is because the solubility of the drug may increase as the temperature rises, but on cooling, the drug will crystallize out. • As shown by Stokes’ equation, the reduction in the particle size of the suspended material is beneficial to the physical stability of the suspension because the rate of sedimentation of the solid particles is reduced. However, one should avoid reducing the particle size too much, because fine particles have a tendency to form a compact cake upon settling to the bottom of the container. The result may be that the cake resists breakup with shaking and forms rigid aggregates that are larger and less suspendable than the original suspended particles.
deflocculated suspension • the dispersed particles remain as discrete separated units and settling will be slow. • The supernatant of this suspension will continue to remain cloudy for an appreciable time after shaking, due to the very slow settling rate of the smallest particles in the product. • The slow rate of settling prevents the entrapment of liquid within the sediment, which thus becomes compacted and can be very difficult to redisperse. This phenomenon is • also called caking and is the most serious • of all the physical stability problems .
flocculated suspension the aggregation of particles in a flocculated suspension will lead to more rapid rate of sedimentation because each unit is composed of many individual particles (i.e., aggregates) and is therefore larger. -One common method of preventing rigid cohesion of the small particles of a suspension (which are responsible for the formation of the cake) is the intentional formation of loose aggregation of the particles. Such an aggregation of particles is termed a floc or a floccule. The floccules have porous loose structure and the dispersion medium can flow through them during sedimentation. Also, they can entrap a large amount of the liquid phase. Therefore, the volume of the final sediment will still be large and will easily be redispersed by moderate agitation. Although flocs settle more rapidly than individual discrete particles, flocculated particles forming a type of lattice that resists complete settling and thus are less prone to compaction and cake formation than unflocculated particles
Flocculating agents Electrolytes: alter the zeta potential of the dispersed particles and, if this value is lowered sufficiently, flocculation may occur. The ability of an electrolyte to flocculate the particles depends on its valency. Although they are more efficient, trivalent ions are less widely used than mono or divalent electrolytes because they are more toxic. electrolytes such sodium salts of acetates, phosphates and citrates. Care must be taken not to add excess electrolyte, otherwise charge inversion may occur Surfactants:Ionic surfactants may also cause flocculation by neutralizing the charge on each particle, thus resulting in a flocculated suspension. Hydrophilic polymers: Starch, alginates, cellulose derivatives, tragacanth and carbomer are examples of polymers that can be used to control flocculation. Their branched-chain molecules form a gel-like network within the suspension Suspending Agents are substances used to make the particles suspended in the vehicle for longer time and slow down their settling by increasing the viscosity of the medium. Carboxymethylcellulose and xanthan gum are example Wetting gents Such as Alcohol and glycerin may be employed as wetting agents. They function by displacing the air on the surface of the particles allowing penetration of water into the powder.