Gels

1. GELS Faraza Javed Mphil Pharmacology

2. What is Gel? Pharmaceutical gels are semisolid systems in which there is interaction (either physical or covalent) between colloidal particles within a liquid vehicle. The vehicle is continuous and interacts with the colloidal particles within the three-dimensional network that is formed by the bonds formed between adjacent particles.

3. The vehicle may be: Aqueous Hydroalcoholic Alcohol based Or Non Aqueous

4. Brief History Franceso Selmi studied Inorganic Colloids in 1840. Modern Colloid Sciences- 1861. Thomas Graham introduced Colloids, Gels, Syneresis etc. Freundlick Research Weiser research on Gel- 1950

5. Gels Criteria The term Gel represents a physical state with properties intermediate b/w those of solids and liquids. It is often wrongly used to describe any fluid system that exhibit some degree of rigidity.

6. Gels Criteria Hermans in 1949 suggested some criteria for Gels: They are colloidal systems of at least two components (the Gelling agent and the fluid component). They exhibit the mechanical characteristics of the solid state. Each component is continuous throughout the system.

7. Structure Of Gels 1. By Dispersion Of Solid Wander walls forces Electrostatic forces 2. By Dispersion Of Polymers Covalent Bonding

8. Types Of Gels Gels are classified in 2 ways. On the Basis of Continuous Phase. On the Basis of Nature of Bond involved in 3 Dimensional Solid Network.

9. Types Of Gels On the basis of continuous phase, gels are classified as: Organogels Hydrogels Xerogels

10. Organogels Solid material composed of liquid organic phase entrapped in three dimensional cross linked network. Non-crystalline Non-greasy Thermoplastic

11. Organogels Uses: In pharmaceutical industry. In cosmetics and food industry.

12. Hydrogels It is a network of polymer chains that are hydrophilic or colloidal gel in which water is the dispersion medium. Highly absorbent Degree of flexibility

13. Hydrogels Uses: As scaffolds in tissue engineering. As environment sensitivity detector. Sustained release DDS. Provide absorption and debriding . Contact lenses. ECG medical electrode. Glue Dressing of healing.

14. Xerogels Gels in which vehicles has been removed, leaving a polymer network (e.g.) polymer film. Use: In DDS

15. Types Of Gels On the Basis of Nature of Bond involved in 3 Dimensional Solid Network. Dispersed solids Hydrophilic polymers i ) Type I ii) Type II

16. Dispersed Solids Dispersed solids will undergo flocculation. The nature of interaction between particles in network may be vander waals or electrostatics interaction. Examples: Al-hydroxide gel USP Kaoline

17. Hydrophilic Polymers Hydrophilic polymers are dispersed within appropriate aqueous phase. Type I: Irreversible system with 3 dimensional network formed by a covalent bonds between macromolecules. Example: Network is formed by polymerization of monomers of water soluble polymer in the presence of cross linking agents.

18. Type II: Reversible system in which interaction occurred between polymers by a hydrogen bonding. Temporary destruction of bonds when stress applied thus formulation enable to flow.

19. Pharmaceutical Consideration Of Pharmaceutical Gels Choice of vehicles Inclusion of buffers Preservatives Antioxidants Flavoring and coloring agents

20. Gelling Agent These are substances which, when added to an aqueous mixture, increase its viscosity without substantially modifying its other properties, such as taste. They provide body, increase stability, and improve suspension of added ingredients.

21. Gelling Agent 3 types of Gelling Agents: 1. Natural Polymers Proteins Polysaccharides 2. Semi synthetic Polymers Cellulose Derivatives 3. Synthetic Polymers

22. Formulation There are 3 methods: Fusion Method Cold Method Dispersion Method

23. Fusion Method In this method various waxy materials employed as gellant in non polar media. Drug was added when waxy materials melted by fusion. stirred slowly until uniform gel formed.

24. Cold Method Water was cooled to 4-10ºc and placed it in mixing container. Gelling agent was slowly added and agitating until solution is complete. Maintained temperature below 10ºc . Drug was added in solution form slowly with gentle mixing. Immediately transfer to container & allow to warm to R.T where upon liquid becomes clear gel .

25. Dispersion Method Gelling agent was dispersed in water with stirring at 1200 rpm for 30 min . Drug was dissolved in non-aqueous solvent with preservative. This solution was added in above gel with continuous stirring.

26. Preparation Of Gels 1 . By freshly precipitating the dispersed phase upon reacting an inorganic agent, a gelatinous precipitate results. Example: Preparation of Al(OH)3 gel is by reacting AlCl3+NaHCo3 .

27. Preparation Of Gels 2. By direct hydrating the inorganic material in water. Al2O3 + H2O Al(OH)3

28. Manufacturing Parameters Order of Mixing: The order of mixing of these ingredients with the gelling agent is based on their influence on the gelling process. If they are likely to influence the rate and extent of swelling of the gelling agent, they are mixed after the formation of gel.

29. Manufacturing Parameters In the absence of such interference, the drug and other additives are mixed prior to the swelling process. In this case, the effects of mixing temperature, swelling duration, and other processing conditions on the physicochemical stability of the drug and additives are also considered.

30. Manufacturing Parameters Ideally the drug and other additives are dissolved in the swelling solvent, and the swelling agent is added to this solution and allowed to swell .

31. Manufacturing Parameters Gelling Medium: Purified water is the most widely used dispersion medium in the preparation of gels. Under certain circumstances, gels may also contain co solvents or dispersing agents. A mixture of ethanol and toluene improves the dispersion of ethylcellulose . Dichloromethane and methanol increase the viscosity of hydroxypropyl cellulose dispersions.

32. Manufacturing Parameters Alcohol improves the rheological stability of polyethylene oxide gels. Inclusion of glycerin, propylene glycol, sucrose, and alcohol improves the dispersion of sodium alginate dispersions.

33. Manufacture Processing Condition The processing temperature, pH of the dispersion, and duration of swelling are critical parameters in the preparation of gels. These conditions vary with each gelling agent.

34. Manufacture Processing Condition For instance, hot water is preferred for gelatin and polyvinyl alcohol, and cold water is preferred for methylcellulose dispersions. Carbomers , guar gum, hydroxypropyl cellulose, poloxamer , and tragacanth form gels at weakly acidic or near - neutral pH conditions (pH 5 – 8).

35. Duration Of Swelling A swelling duration of about 24 – 48 hours generally helps in obtaining homogeneous gels. Natural gums need about 24 hours and cellulose polymers require about 48 hours for complete hydration.

36. Removal Of Entrapped Air Entrapment of air bubbles in the gel matrix is a common issue. Especially when the swelling process involves a mixing procedure or the drug and other additives are added after the swelling process.

37. Removal Of Entrapped Air Positioning the propeller at the bottom of the mixing container minimizes this issue to a larger extent. Further removal of air bubbles can be achieved by long - term standing, low-temperature storage, sonication , or inclusion of silicon antifoaming agents. In large-scale production, vacuum vessel deaerators are used to remove the entrapped air.

38. Examples Of Topical Gels No. Active Ingredients Proprietary Gelling Agent Route & Use 1. Clindamycin Cleocin T Gel Carbomer Acne Vulgaris 2. Cyanocobalamin Nascobal Methyl Cellulose Nasal: Hematologic 3. Metronidazole Metro-Gel Carbomer Vaginal: Bacteria 4. Progesteron Suppliment Crinone -Gel Carbomer Progesteron 5. Tretinion Cellulose Retin -A Hydoxypropyl Cellulose Acne Vulgaris

39. Properties Of Gels Swelling Syneresis Ageing Adsorption of vapours by Xerogel Rheological properties Chemical reactions in gels Diffusion in gels

40. Swelling

41. A P A A P A A P A A P A A A A A A A A A A NETWORK SWELLING: DRUG CAN BE RELEASED P A A P A A P A A P A A = DRUG A =ANALYTE P = PROTEIN

42. Depends On: No. of linkages b/w molecules of gelling agent. Strength of linkages e.g. iso -electric point Presence of ions in swelling liquid e.g. Sulphate ions increases resistance to swelling by forming additional linkages.

43. Network consisting of primary valence bond e.g. in SILICIC ACID GEL the strength of bond is sufficient to prevent swelling.

44. Syneresis “ The contraction of the gel to exude some of the fluid medium” Depends On: Conc. Of the gelling agent i.e. syneresis decreases as the conc. of gelling agent increases. Thermodynamic stability or unstability . Example: Blood clot is common example of syneresis .

45. Ageing “ The slow spontaneous aggregation” In gels ageing results in formation of denser network of gelling agent. Experiment: Theimer (1960) observed formation of additional thin fibrils in 10 days old gelatin gels as compared with a fresh gel. Further little change in structure after 21 days since dehydration processes were slowing down.

46. Adsorption Of Vapors By Xerogels Porous nature of xerogel leads to increased surface area as well as increased adsorption e.g. SILICA GEL used therefore as drying agent. The hysteresis loop b/w curves showing absorption and desorption shows variations in vapor uptake at different equilibrium processes.

47. Reason Pores are filled with liquid in ABSORPTION. Pores are emptied in DESORPTION.

48. Chemical Reactions In Gels

49. Diffusion In Gels The soluble substances tend to permeate through gel by diffusion. Rate Of Diffusion Depends On: Diffusion in solution Presence of gel network

50. Diffusion In Solution “Spontaneous transference of solute from regions of higher conc. to lower conc. until uniform distribution”. Rate Of diffusion of solute explained by Fick’s first law: dm = - DAdc dt dx D of spherical particles is given by Sutherland Einstein equation: D = RT/6ŋrNa

51. Presence Of Gel Network Sieve Effects: When the size of diffusing particles becomes larger than the pores the diffusion is retarded and ceases . It depends on conc. of gelling agent and the age of the gel. Other Effects: Adsorption of the diffusing solute onto the walls of the pores will retard the rate of diffusion. The viscosity of liquid components in the pores is important not the overall viscosity of the gel.

52. Evaluation Of Gels pH determination Drug content Viscosity Spreadability Extrudability study In vitro release Stability

53. Drug content Amount of drug = conc. × dilution factor × conversion factor %age purity = Amount of drug × 100 Labeled claim

54. Spreadibility S = M. L/M M = wt. tied to upper slide L = Length of glass slide T = Time taken to separate the slides

55. Extrudability Studies Extrudability = Applied wt. to extrude gel from tube Area (in inches)

56. Application Of Gels Glycogelatin gels are used as a basis for medicated pestilles . Formulation of some suppositories e.g. Glycerin suppositories B.P. Used in Hard and soft gel capsules. Gelatin gels use as solid media for the culture of microorganisms.

57. Application Of Gels Avoid oral drug degradation Extend the product for economical reasons e.g. paint Used in gel filtration Aerogels

58. References Tutorial Pharmacy Edited by S.J. Carter. Pharmaceutical Dosage Form by Howard C. Ansel . Bentley’s Book Of Pharmaceutics, 8 th Edition, Edited by E.A Rawlion . Aulton’s Pharmaceutics, 3 rd Edition, Edited by E. Aulton . Pharmaceutics Dosage Form & Design by David Jones. www.pubmed.com www. Pharmainfo.net/reviews/topical-gels www.arjournals.org