Lectu-9-Susp Clinical Prof. Alaa Zaky Fall 2024 PDF

IX Dosage Form 1 (PT303) Pharm D Clinical Suspension Dr. Alaa Zaky Prof. of pharmaceutics & Pharmaceutical Technology IV- Compounds Allowing Control of Stability and Sedimentation: Flocculating agents Suspending agents A - Flocculating agents ❖ Flocculation mu...

IX Dosage Form 1 (PT303) Pharm D Clinical Suspension Dr. Alaa Zaky Prof. of pharmaceutics & Pharmaceutical Technology IV- Compounds Allowing Control of Stability and Sedimentation: Flocculating agents Suspending agents A - Flocculating agents ❖ Flocculation must be controlled to prevent formation of compact sediment and difficult to redisperse. In flocculated systems (where the repulsive barriers have been flock reduced) Particles form loosely bonded structures (flocs or flocculates). The particles therefore settle as flocs and not as individual particles. Because of the random arrangement of the particles in the flocs, the sediment is not closely packed and caking does not readily occur. In deflocculated systems the particles are not associated(connected); pressure on the individual particles cake can lead to close packing of the particles at the bottom of the container and become irreversibly bound together to form a cake. Caking of the suspension is usually prevented by including a flocculating agent in the formulation.  (a) Deflocculated suspension (b) Focculated suspension Sedimentation of (a) deflocculated and (b) flocculated suspensions.  Controlled Flocculation Flocculation: Formation of a loose aggregation of discrete particles held together in a network like structure by physical adsorption, bridging or when the van der wall forces of attraction exceed forces of repulsion. The stable flocs contain varying amounts of entrapped liquid medium within the network like structure. (Flocculated suspensions)  Flocculating Agents addition of non ionic wetting agent lead to a deflocculated suspension due to hydrated hydrophilic layer around each particles forming a mechanical barrier Use of flocculating agent Defloc. susp Floc.susp Flocculating agents decreases zeta potential of the suspended charged particle and thus cause aggregation (flock formation) of the particles.  Controlled flocculation Flocculating agents 1-The use of inorganic electrolytes or ionic surfactants to control zeta potential (addition of an adsorbed ion whose charge is opposite to the sign of the particles so particles approach each other and form loose aggregates or flocs. 2- The addition of polymers to enable cross linking to occur between particles. Flocculating agents used for this purpose include: Electrolytes Surfactants Polymers 1- Electrolytes Electrolytes act as flocculating agents by reducing the electrical barrier between the particles, as evidenced by a decrease in the zeta potential and the formation of a bridge between adjacent particles so to link them together in a loosely arranged structure. When particles of bismuth subnitrate were dispersed in water, it was found that, they, possess a large positive charge, or zeta potential. Because of the strong forces of repulsion between adjacent particles, the system is peptized or deflocculated. The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles, adsorption of the negatively charged phosphate anion causing the positive zeta potential to decrease. With the continued addition of the electrolyte, the zeta potential falls to zero and then increases in a negative direction The onset of flocculation coincides with the maximum sedimentation volume determined. “F” remains reasonably constant while flocculation persists, and only when the zeta potential becomes sufficiently negative to effect re peptization does the sedimentation volume start to fall.  1- Electrolytes - - Dispersion of bismuth subnitrate - - - - ++ + _ - - ++ K + phosphate + + + + _ - _ xss - + + + po4 - - - - ++ ++ ++ + + _ Adsorption of –ve + _ + charge high zeta + _ potential + + deflocculated ++ + _ system hard cake small vu/vo High zeta potential Adsorption of –ve charge zeta potential=0 Deflocculated system Particles loosely linked Slow sedimentation Flocculated system no hard cake,Small vu/v0 cake, high vu/v0 Caking diagram, showing the flocculation of a bismuth subnitrate suspension in which Monobasic potassium phosphate was employed as flocculating agent. " http://www.medicinescomplete.com/mc/rem/current/images/c36-fig-36-3.png Similarly, sulfamerazine suspension (-ve charged) can be flocculated by aluminum chloride (+ve flocculating agent).  The most widely used electrolytes include; – the sodium acetates, phosphates and citrates – N.B Trivalent electrolytes are more efficient than mono & divalent electrolytes. BUT, they are less widely used due to their high toxicity. Also if hydrophilic polymers are used in the formulation, will be precipitated by trivalent ions. Conc. used must be adjusted according to the required degree of flocculation. If add excess electrolytes: charge reversal & formation of deflocculated system 2- Surfactants Surfactants have been used to bring about flocculation of suspended particles. The concentration necessary to achieve this effect is critical since these compounds may also act as wetting agents to achieve dispersion. 1. Ionic surface-active agent – May also cause flocculation by neutralizing the charge on each particle, thus resulting in a flocculated system. 2. Non-ionic surfactants, – Have a negligible effect on the charge density of a particle but may, because of their linear configurations, they adsorb more than one particle on their surfaces, thereby forming a loose flocculated structure.  3-Polymers Hydrophilic polymer acts Long chain high MWt as Protective colloid in con ˂ 0.1% Bridging Adsorbed on surface less between liable to cake than uncoated particles to have pseudoplastic flow form flocs helps in suspending Mechanism of polymer floc formation 1. Polymers possess long chain in their structures. Starch, alginates, cellulose derivatives, carbomers, tragacanth 2. The part of the long chain is adsorbed on the surface of the particles and remaining part projecting out into the dispersed medium. Bridging between these later portions, also leads to the formation of flocs. 3- Polymers E.g., Starch, alginates, cellulose derivatives, tragacanth, carbomers and silicates. Mechanism:-Their linear branched-chain molecules form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles, thus holding them in a flocculated state. Polymers are long chain, high molecular weight compounds containing active groups spaced along their length. These agents act as flocculating agents because part of the chain is adsorbed on the particle surface with the remaining parts projecting out in the dispersion medium. Bridging between these portions leads to the formation of floccules. B- Viscosity Modification Suspending Increase Decrease agent viscosity sedimentation e.g. Carboxymethylcellulose (CMC), Carbopol, Tragacanth, or Bentonite either alone or in combination. Why we need to modify the viscosity in suspension formulation?? 1. Viscosity can affect settling of the suspended particles. 2. Change in flow properties when container is shaken or product pour from the bottle. 1. Spreading of topical products applied to skin. Suspending agents (viscosity modifier) increase the viscosity of the vehicle, thereby slowing down sedimentation.  Suspending Agents 1. organic 2. Inorganic 3. synthetic Clays (bentonite, e.g. carbomers or veegum) carbopols Colloidal silicon Natural Semi synthetic dioxide or aerosil Hydrophilic colloid Such as Cellulose derivatives :eg (acacia, tragacanth, sodium sodium CMC, methyl alginate) in conc > 0.1 carry cellulose, microcrystalline –ve charge cellulose, hydroxyethyl cellulose  Classification of suspending agents 1.Natural polysaccharides( Natural hydrophilic colloid); e.g., Tragacanth, acacia, starch and alginate. 2.Semi-synthetic polysaccharides ( water soluble cellulose); e.g., methyl cellulose (Natrosol 250); Hydroxyethyl cellulose; Na carboxy methyl cellulose (Carmellose) and Microcrystalline cellulose (Avicel). 3. Clays (hydrated silicates); They are natural inorganic materials which are mainly hydrated silicates, e.g., Bentonite (2-3%); and Magnesium aluminium silicate(veegum) (5%) which have pseudoplastic thixotropic character. Classification of suspending agents 3.Synthetic thickeners; those were introduced to overcome the variability of quality of natural products, e.g., Carbomer; Polyvinyl alcohol; Colloidal silicon dioxide. 4.Miscellaneous compounds: e.g., Gelatin. Although glycerin and hydrophilic polymers have high viscosity only hydrophilic polymers are used as suspending agent…..Why? Because Glycerin is newtonian, has constant viscosity on rest and shaking and sticky, but hydrophylic polymers are pseudoplastic  Hydrophilic colloid polymer Acts as protective colloid (in conc 0.1 Problem of using suspending agents Incompatibilities between flocculating and suspending agent This may lead to incompatibilities, depending on the initial particle charge and the charge carried by the flocculating agent and the suspending agent. For example: Suppose we prepare a dispersion of +vely charged particles that is then flocculated by the addition of the correct concentration of a –vely electrolyte such as KH2PO4. To improve the physical stability of this system add minimal amount of a hydrocolloid mentioned. No physical incompatibility will be observed because the majority of hydrophilic colloids are themselves -vely charged and thus compatible with anionic flocculating agents. If we flocculate a suspension of -vely charged particles with a cationic electrolyte (AlCl3), the subsequent addition of hydrocolloid may result in an incompatible product, as evidenced for the formation of an unsightly string mass that has little or no suspending action and itself settles rapidly.  + -+ -+ + Negatively charged + + + KH2PO4 + + + + flocculating agent - +- Compatible with the negatively charged hydrophilic colloids N.B. Hydrophilic colloids are used to improve physical stability of the suspension by increasing its viscosity. So: No incompatibility between hydrocolloid and anionic flocculating agent  -- + -+ -+ Positively charged - - - - AlCl3 - - flocculating agent - +- incompatible with the negatively charged hydrophilic colloids Formation of an unsightly string mass that has little or no suspending action and itself settles rapidly Solve the incompatibility between hydrocolloid and cationic flocculating agent by the use of: 1- Non ionic surfactant as flocculating agent. 2- Long chain polymers as flocculating agent. The Ideal Suspending Agent: Have a high viscosity at negligible shear, i.e., during shelf storage. Have a low viscosity at high shearing rate, i.e., it should be free- flowing during agitation, pouring, spreading and injecting. Pseudoplastic substances such as: tragacanth, sodium alginate, and sodium carboxymethyl cellulose show these desirable qualities. The Newtonian liquid, glycerin,: its viscosity is suitable for suspending particles. BUT It is too high to pour easily and to spread on the skin. It shows the undesirable property of stickiness. It is too hygroscopic to use in undiluted form. V- Formulation additives 1. Buffers – Maintain chemical stability, control tonicity, – Or ensure physiological compatibility. 2. Humectants – Prevent drying of product after application to the skin. e.g. glycerol and propylene glycol (at conc. 5% into aqueous suspension). 3. Flavors, Colors and Perfumes 4. Preservatives – To prevent growth of m.o. that may be present in raw material & or introduced during use, e.g benzoic acid (at pH less than 5, conc. 0.1%, oral use). Sorbic acid (at acidic pH, conc. 0.1-0.2%, oral use) 5. Sweetening agents To mask bad taste of drug and have a palatable product. e.g. Sucrose (the most widely used). Artificial sweeteners sodium, calcium salts of saccharin. aspartame.  Components Function API Active pharmaceutical ingredient Wetting agents They are added to disperse solids in continuous liquid phase. Flocculating agents They are added to floc the drug particles Thickeners They are added to increase the viscosity of suspension. Buffers They are added to stabilize the suspension to a desired pH and pH adjusting agents range. Osmotic agents They are added to adjust osmotic pressure comparable to biological fluid. Coloring agents They are added to impart desired color to suspension and improve elegance. Preservatives They are added to prevent microbial growth. External liquid vehicle They are added to construct structure of the final suspension.  Question Some suspensions should be sterilized before use??? Because it may contain an agent containing a m.o., E.g. Bentonite (suspending agent) may contain Clostridium tetani (a hazardous m.o. esp. if the product applied on a broken skin). SO, sterilize by heating the dry powder at 160‘C for 1 hour or, autoclave the aqueous dispersions. N.B: Care must be taken to ensure that the activity of any of the ingredients is not destroyed by the sterilization process.  Evaluation of Suspensions Evaluation techniques permits the formulator to screen the initial preparations made and also to compare commercial products. 1. Sedimentation volume "F“. 2. Degree of flocculation "B“. 3. Redispersability: This was determined by the number of upside down inversions of the suspension contained in a measure. The smaller the number, the easier would be the redispersability of the sediment. A number greater than 15 inversions indicated caking. 4. Rheological Characteristics: The flow of the acceptable suspension will be either pseudoplastic or plastic & it is desirable that thixotropy be associated with these two types of flow.