Parenteral suspensions

Short review about parenteral suspension, principle consideration during formulation, factors affecting formulation etc. are included in this presentation.

1. Parenteral suspensions by- Tahib Habshi

2. Learning outcomes

3. Definition Parenteral suspension are dispersed, heterogeneous systems containing insoluble drug particles which when re-suspended in either aqueous or oil vehicles before administration to a patient . They are administered via different parenteral routes such as I.V, I.M, S.C etc. Examples of such routes Insulin zinc suspension (S.C), Paclitaxel suspension (I.V), Procaine penicillin G suspension (I.M).

4. These are intended for administration only by injections . These suspensions have long time actions. Active drug substance must be suspended with water for injection . These suspensions may show sediment which is readily dispersible upon shaking.

5. Reason for development The drugs which are insoluble and are difficult to be formulated as SOLUTION. T he drugs which are more stable when suspended than in solution form. When there is a need to develop dosage forms having retarded or controlled release of drugs. The larger surface area of dispersed drugs may help ensure a high degree of availability for absorption.

6. Ideal properties It must be sterile during storage and use. Syringeability and injectability are closely related with viscosity and particle characteristics. Particle size should be small and uniform . Re-suspension of particle occurs easily. Dispersed particles do not settle rapidly after shaking. Cake formation must not occur during its shelf life. It must be isotonic and non-irritating . Its should contain 0.5-5.0% solids and particle size less than 5 µm . Maintain its stability and elegance during its shelf life.

7. Pharmaceutical Standards They should be sterile, pyrogen free, stable, re-suspendable, syringeable, injectable, isotonic, non-irritable. Because of above requirements, parenteral suspensions are the most difficult dosage form to be develop . They may be formulated as a ready to use injections or require a reconstitution step prior to use. Newer suspension delivery systems containing drugs in microparticles or nanoparticles can be used as I.V, I.M, S.C etc.

8. These suspensions must usually contain between 0.5-5.0% solids and particle size less than 5 µm for I.M or S.C administration.

9. A dvantages Better for drugs which are insoluble in convection solvents. Increased resistance to hydrolysis and oxidation as is susceptible. Provides chemical stability . larger surface area is available as microparticles or nanoparticles used to provide better absorption . Controlled release or sustained release of drug is possible.(protamine zinc-insulin suspension) Elimination of hepatic FPM .

10. Disadvantages There may be chances of non-uniformity of dose at the time of administration. Maintenance of physical stability is very difficult in this dosage form. Stabilization of suspensions for period between manufacture and use may face problems such as sedimentation, cake formation, difficulty in redispersion . Difficulty in formulation such as selection of ingredients. Special facilities are required such as aseptic area for process such as crystallization, size reduction, sterilizations.

11. Formulation consideration Interfacial properties: Interfacial properties of dispersed particle such as the increase in the specific surface area with reduction in particle size and the presence of electrical charge on the surface of particles play major role in stability. ∆ 𝐺= change in surface free energy in ergs 𝜒𝑠/u = interfacial tension in dyne/cm 2 dispersed particles and medium ∆ 𝐴= change in surface area in cm 2  

12. As the particle sizes is reduced where there is increased in surface area which causes high surface free energy due to which clumping of particles occur. In order to make an stable system , high surface free energy is reduced , which minimizes the interfacial tension. This is done by using surface active agents .

13. Flocculation and Deflocculation The charges at the shear plane associated with the particles surface is described as the zeta potential. When the zeta potential is high , results in deflocculated particles. This particles settles at slow rate and forms a hard cake which cannot easily redispersed . So this is overcome using flocculating agents eg . Salts, organic polymers etc. causing the formation of loose aggregates.

14. Flocculated suspensions are the more common type of parenteral suspension because most injectables suspensions contains low concentration of solids, less viscous and have less zeta potential to produce stability problems. Unless, this deflocculated phenomena is applicable in the suspension contains high solid concentrations such as procaine penicillin G contain 30% solid particles.

15. Stock’s law This law shows information based on sedimentation rates of solid particles. Thus increase in the viscosity of liquids or decreasing particles size minimizes the sedimentation rate which Is an important factor in the stability of suspension. Where, 𝑠 = sedimentation rate in cm/sec d = diameter of particles in cm  

16. 𝑃𝑠= density of dispersed phase 𝑃𝑖= density of dispersed medium g= gravity constant 𝜂= viscosity in poise.

17. Crystal Growth Crystal growth is a major stage of a crystallization process which typically follow an initial stage of either homogeneous or heterogeneous nucleation . The following factors affect the potential for crystal growth in suspension. Particle size distribution. Dissolution and recrystallization. Changes in pH and temperature.

18. Variable particles size distribution result from various including: Preparation of suspension by precipitation methods where the degree of super saturation and the rate of nucleations are greatest at the beginning of the process results in large particles formation initially and smaller particles formation. Change in pH caused due to drug decomposition. Temperature changes cause the nucleation which will lead to crystal formation.

19. Thus, to minimizes the crystal growth, particles size distribution, viscosity, use of right polymorph, solvent, temperatures cycles study, to evaluate the physical and chemical stability of suspension .

20. Caking/ Cake formation. The inability of re-suspended drug particles upon caking result from particles settings as a hardened sediment call a “cake”, occurs when attractive between solid particles and vehicles are greater.

21. Factors affecting formulation Solubility of drugs in biological fluids at injection site. Lipid solubility and oil water partition coefficient. pKa , pH of drugs. Particles size. Compatibility. Solvates and polymorphs. pH stability. Tonicity. Dissolution rate.

22. Excipients used in parenteral suspensions Flocculating agents/ suspending agents- e.g. hydro colloids, electrolytes, organic polymers, surfactants, etc. Wetting agents - e.g. non-ionic surfactant, organic polymers, etc. Solvent s- aqueous or non aqueous solvents. Preservative s- e.g. benzyl alcohol, parabens, etc. Anti-oxidants/chelating agents- e.g. ascorbic acid, sodium bisulfite, tocopherols.

23. Tonicity agents- e.g. dextrose and other electrolytes Preservatives - e.g. benzyl alcohol, parabens, etc.

24. Thank you