Parenteral Formulations products requirements

FORMULATION OF PARENTERAL PRODUCTS REQUIREMENTS, FORMULATION DEVELOPMENT, PRETREATMENT OF WATER ,REVERSE OSMOSIS ,STERILE WATER FOR INJECTION USP ,PYROGENS,

1. FORMULATION OF PARENTERAL PRODUCTS

2.   REQUIREMENTS Only liquids can be injected which means that the pharmaceutical parenteral preparation must either be a liquid which can itself be injected safely, or it may be a material that can be diluted with sterile water (commonly referred to as ‘water for injection’) or other sterile solvent before it is administered. Liquids other than water must not interfere with the stability and efficacy of the preparation. Parenteral preparations may require the use of excipients such as Solvents, Substances to enhance solubility, FORMULATION OF PARENTERAL PRODUCTS

3. Suspending agents, Buffering agents, Substances to make the preparation isotonic with blood, Stabilizers or antimicrobial preservatives. The addition of excipients is kept to a minimum. There must be no incompatibility between any of the components of the dosage form. Water for injections is used as the vehicle for aqueous injections. Sterilization at this stage may be omitted, provided that the preparation is subject to terminal sterilization. For non-aqueous injections, fixed oils of vegetable origin are used as vehicles.

4. Unless otherwise specified in the individual monograph, sodium chloride or other suitable substance(s) may be added to an aqueous solution for injection in order to render the preparation isotonic. When excipients are used they do not adversely affect the stability, bioavailability, safety or efficacy of the active ingredient(s), or cause toxicity or undue local irritation Some substances may be added to increase the stability and efficacy of the preparation, but it is important that such additives do not cause adverse effects or toxicity. Coloring agents are not permitted in parenteral preparations

5. If parenteral preparations are to be stored in multiple dose containers, antimicrobial preservatives may be added to the formulations, which prevents and inhibits the growth of microbes in the container. Also, if the active ingredient(s) have the potential to oxidize and degrade, manufacturers can add anti-oxidants to the parenteral preparation, or the air in the container in which it is to be stored may be eliminated by evacuation, or displaced with nitrogen or other inert gas. The pH is one of the critical aspects of parenteral preparations, which should have a pH close to the physiological one.

6. In all cases, large volumes preparations—LVP, i.e. more than 100 ml as defined in pharmacopeia—should not contain a pH buffer as the blood already has a buffer effect property that could enter into competition with the injected drug product.

7. Formulation Development Formulation Principles The formulation of parenteral preparations need careful planning ,thorough knowledge of medicaments and adjuvants to be used. The excess use of adjuvants in parenteral products should be avoided as some of these may interfere with the drug. Formulation of parenterals includes 1 Vehicles  2 Adjuvants  A) solubilizing agents 

8. B) Stabilizers C)Buffering agents D) Antibacterial agents E) Chelating agents F) Suspending ,emulsifying and wetting agents G) Tonicity adjusting agents .

9. I.VEHICLES Vehicles are the liquid phase used in formulation of parenterals . Solvents & vehicles must meet special purity & other standard to assure sterility, stability and safety. Vehicle used should be:  Pharmacologically inert,  Non toxic and compatible with blood,  Maintain solubility of the drug,  Be physically and chemically stable,  Does not affect the pH,  Must be pyrogen free,  Contain no particulate mater,  The finished product must meet sterility standard.

10. a)AQUEOUS VEHICLES The vehicle of greatest importance for parenteral products is water. Water is preferred because : Generally water for injection is used as vehicle, unless otherwise specified. WATER FOR INJECTION, USP Water for injection by definition is water that is intended for use in the manufacture of parenteral (i.e. injectable) drugs whose solvent is water. The USP (United States Pharmacopeia) defines this as highly purified waters containing less than 10 CFU/100 ml of Aerobic bacteria. These waters should also have fewer than 500 ppb of total organic carbon, fewer than 0.25 EU/ml endotoxins, and a conductivity of less than 1.3uS/cm @ 25 C.

11. PRODUCTION of WFI USP allows WFI to be produced by one of two means; either distillation or reverse osmosis. Distillation Still What happens in a WFI still? When water is distilled, it is heated until it becomes a vapor, stripping the heavier ions, particulates, and endotoxins from the water. There are both single and multiple effect stills

12. Multicolumn Distillation Plant The pre-heated feed water (through condenser) is fed into the first column where 33% of feed water is converted into steam under pressure by outside boiler steam. The pure steam produced in the first column having temperature of 135’c and the remaining feed water goes to the 2nd column. The pure steam is used as a heating media in the 2nd column and converts part of remaining feed water into steam. In the process the steam itself condenses back into water. This process is repeated till the last columns each working at low temperature & pressure as compared to the one before it. The steam produced in the last column is condensed in the condenser by feed water as well as cooling water. As external heat is required only to convert the 33% of feed water, the heating energy required is reduced by 67%

13. Pretreatment of Water Prior to making it to the still, however, supply water has to go through extensive pretreatment. Pretreatment usually includes various filtration steps, removal of particulate matter through the use of sand filter ,removal of chlorines through the use of activated carbon beds, and percolation of water through ion exchange resins to remove residual ionic compounds. What is the purpose of all this pretreatment? By pretreating the water, we effectively reduce the conductivity of the water, as well as the level of organic contaminants. Once the water makes it through these pretreatment steps, it goes to the still.

14. Reverse osmosis We can also get WFI from a process called reverse osmosis. Reverse Osmosis is the process of Osmosis in reverse . Whereas Osmosis occurs naturally without energy required, to reverse the process of osmosis you need to apply energy to the more saline solution. A reverse osmosis membrane is a semi-permeable membrane that allows the passage of water molecules but not the majority of dissolved salts, organics, bacteria and pyrogens. However, you need to 'push' the water through the reverse osmosis membrane by applying pressure that is greater than the naturally occurring osmotic pressure in order to desalinate (demineralize or .

15. deionize) water in the process, allowing pure water through while holding back a majority of contaminants

16. WFI Storage and Distribution What is to be done with WFI after it is produced to ensure the water stays at water for injections quality? It either needs to be used quickly (usually same day) or put in a state that allows it to maintain its efficacy. How do you make sure WFI stays as WFI? You need to minimize microbial growth. This is accomplished by maintaining it at high temperatures and keeping it in motion.  Normally WFI is kept at 90 degrees C and recirculated through a distribution loop at a minimum velocity of 5 feet per second

17. STERILE WATER FOR INJECTION USP •Water for injection which has been sterilized & packed in container of 1 Liter or less •Pyrogen free •No antimicrobial preservation or added substances •Intended to be used as a solvent, vehicle or diluent for already sterilized & packed injectable •Must be added aseptically

18. water for injection ,contaminated with pyrogens may cause rise in body temperature if injected . Hence, test for pyrogen is done to ensure that water for injection is free from pyrogens.

19. What are Pyrogens? A Pyrogen is defined as “a fever producing agent” Metabolic products of Microorganisms. Many bacteria, molds and viruses produce pyrogens Gram – ve bacteria produce the most potent pyrogenic substances as endotoxins ( e.g., Pseudomonas sp , Salmonella sp, Escherichia coli). Gram-positive bacteria and fungi also produce pyrogens but of lower potency and of different chemical nature. Chemically pyrogens are lipid substances associated with a carrier molecule ,which is normally polysaccharide but may be peptide They are Soluble ,Filterable, Thermostable and Non Volatile.

20. I hr after injection into human body they will produce marked increase in body temperature ,chills ,body aches and rise in arterial blood pressure. Fever response to pyrogens in rabbits is the bbasis for official pyrogen test . Pyrogens are Endogenous (inside body) Exogenous (outside body) Exogenous pyrogens  They are foreign substance that are derived outside the host.  Lipopolysaccharides and other substances produced by pathogenic microorganisms.

21. These substance becomes pyrogens when they are administered parenterally to the host. They can be subdivided into the two group; Microbial pyrogens  Nonmicrobial pyrogens  Endogenous Pyrogens  Produced by the immune cells that are activated by the presence of infectious agents (e.g. bacteria, viruses )  Endogenous pyrogens are usually cytokines, such as interleukin-6, interleukin-1, tumour necrosis factor, interferon-alpha, gp130 Receptor Ligands, and so on

22. Sources of Pyrogens Most likely sources are water ,contaminated solutes and containers

23. Removal Of Pyrogens 1.Pyrogens can be removed from water by simple distillation process using an efficient trap which prevents the pyrogen to enter into the condenser . Immediately after the preparation of water for injection ,it is filled in to the final container, sealed and sterilized by autoclaving . us 2. Solutes must be prepared from vehicles free from pyrogens and must be stored in a manner designed to prevent subsequent contamination . 3. Containers may be rendered free from pyrogens by adequate cleaning and heating usually at 210°C for 3 to 4 hrs

24. b) Non Aqueous Vehicles i.Water -Miscible Vehicles A number of solvents that are miscible with water have been used as a portion of the vehicle in the formulation of parenterals . These solvents are used to solubilize certain drugs in an aqueous vehicle and to reduce hydrolysis. Desired / required vehicle properties –No irritation, sensitization, toxicity or pharmacological activity –Should not affect the activity of the drug –Should have suitable physicochemical properties for intended use (stability, viscosity, fluidity with temperature, boiling point, miscible with body fluid, low vapor pressure). –Purity (ease of purification & standardized). –Must remain clear at 10°C

25. The most important solvents in this group are Ethyl alcohol, Glycerin, Liquid polyethylene glycol and Propylene glycol. Ethyl alcohol is used in the preparation of solutions of cardiac glycosides and the glycols in solutions of barbiturates, certain alkaloids, and certain antibiotics. Such preparations are given intramuscularly

26. 2. Ethyl alcohol is used in the preparation of hydrocortisone injection . Hydrocortisone is insoluble in water ,hence the solution is made in50% alcohol . Alcohol causes pain and tissue damage at the site of injection . Therefore it is not used commonly. 3.Propylene glycol is used as a vehicle in the preparation of degoxin injection .it is relatively non-toxic but it causes pain on s/c or I/M injection.

27. 4.Polyethylene glycol (PEG)and Glycerine usually diluted with sterile water are used to prepare solutions for injections . They are used as solvent as well as to increase the stability of certain preparations

28. ii. Water Immiscible Vehicles The most important group of non-aqueous vehicles is the fixed oils. The USP provides specifications for such vehicles, indicating that the fixed oils must be of vegetable origin so they will metabolize, will be liquid at room temperature, and will not become rancid readily. The USP also specifies limits for the free fatty acid content, iodine value, and saponification value (oil heated with alkali to produce soap, i.e., alcohol plus acid salt). Oils most commonly used are Corn oil, Cottonseed oil,

29. II. Adjuvants/Added Substances The USP includes in this category all substances added to a preparation to improve or safeguard its quality These adjuvants should be used only when it is absolutely necessary to use them. While selecting the additives ,care must be taken that they should be compatible both physical and chemical with the entire formulation They should be added in minimum possible quantity .

30. An added substance may: 1.Increase and maintain drug solubility. Examples include Complexing agents and Surface active agents. The most commonly used complexing agents are the cyclodextrins , Cyclodextrins  (similar to the larger cycloamyloses , which are typically composed of at least 17 units) are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides). Cyclodextrins  are produced from starch by enzymatic conversion conversion. The most commonly used surface active agents are polyoxyethylene sorbitan monolaurate (Tween 20) and polyoxyethylene sorbitan monooleate (Tween 80).

31. 2.Provide patient comfort by reducing pain and tissue irritation, As do substances added to make a solution isotonic or near physiological pH. Common tonicity adjusters are sodium chloride, dextrose, and glycerin 3.Enhance the chemical stability of a solution As do antioxidants, inert gases, chelating agents, and buffers. 4.Enhance the chemical and physical stability of a freeze dried product , As do cryoprotectants and lyoprotectants .

32. Common protectants include sugars, such as sucrose and Trehalose ( Trehalose  is a sugar consisting of two molecules of glucose. It is also known as mycose or tremalose . Some bacteria, fungi, plants and invertebrate animals synthesize it as a source of energy, and to survive freezing and lack of water ) , and amino acids, such as glycine. 5.Enhance the physical stability of proteins By minimizing self-aggregation or interfacial induced aggregation. Surface active agents serve nicely in this capacity.

33. 6.Minimize protein interaction with inert surfaces , such as glass and rubber and plastic . Competitive binders, such as albumin, and surface active agents are the best examples 7.Protect a preparation against the growth of microorganisms . Antimicrobial Agents USP states that antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple-dose containers. European Pharmacopeia requires multiple-dose products to be bacteriocidal and fungicidal.

34. Example Benzethonium chloride and benzalkonium chloride 0.01%, Phenol or cresol 0.5%and chlorobutanol 0.5%. The above limit is rarely used for phenylmercuric nitrate, most frequently employed in a concentration of 0.002%. Methyl p- hydroxybenzoate 0.18% and propyl p- ydroxybenzoate 0.02%, in combination, and benzyl alcohol 2% are also used frequently. Benzyl alcohol, phenol, and the parabens are the most widely used antimicrobial preservative agents used in injectable products Single-dose containers and pharmacy bulk packs that do not contain antimicrobial agents are expected to be used promptly after opening or discarded. Large-volume, single-dose containers may not contain an added antimicrobial preservative

35. The following other adjuvants are commonly used in preparing stable parental preparations:- a)Solubilizing agents:- These are used to increase the solubility of drugs which are slightly soluble in water . The solubility of drug is increased by using surface active agent like Tweens and Polysorbates or by using co solvents. b)Buffering agents:- The degradation of the preparation which is due to change in pH can be prevented by adding a suitable buffer to maintain the desired PH . Maintaining of the pH is very important for avoiding irritations that may be produced if pH is not maintained properly For example citric acid and sodium citrate ,acetic acid and Sodium acetate .

36. c) Stabilizers:- the drugs in the form of solution are more liable to deteriorate due to oxidation and hydrolysis . The stabilizers are added in the formulation to prevent this . Oxidation can be prevented by adding a suitable antioxidant such as, Thiourea , Ascorbic acid ,Sodium meta bi sulphite ,or the product is sealed in an atmosphere of Nitrogen or Carbon dioxide. Hydrolysis can be prevented by using a non aqueous vehicle or by adjusting the pH of the preparation Antioxidants They are substances which improves the stability of the preparation by delaying the oxidation of the API and other excipients present in the formulation.

37. Examples of such antioxidants are ascorbic acid and sodium bisulfite etc. Antioxidants are classified into three groups True antioxidants: They inhibit oxidation by reacting with free radicals and blocking chain reactions. Reducing agents: These substances have lower redox potentials than the API and the excipients that they are intended to protect. Therefore, they get themselves oxidized. They also operate by reacting with free radicals.

38. Antioxidant synergists: They have less antioxidant property themselves, but they enhance the antioxidant property of the first group by reacting with the heavy metal, ions that catalyze oxidation. d)Tonicity agents An  isotonic  solution refers to two solutions having the same osmotic pressure across a semipermeable membrane. This state allows for the free movement of water across the membrane without changing the concentration of solutes on either side. Parenteral preparation should be isotonic with blood plasma or other body fluids

39. TONICITY AND ISOTONICITY Tonicity is a property of a solution in reference to a particular membrane, and is equal to the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across the membrane. Tonicity depends on solute permeability. The permeable solutes do not affect tonicity. If a semi- permeable membrane is used to separate solutions of different solute concentrations, a phenomenon known as osmosis occurs to establish concentration equilibrium.

40. The pressure driving this movement is called osmotic pressure and governed by the number of particles of solute in a solution Tonicity is generally classified in three types: 1. Hypertonicity 2. Hypo tonicity 3. Isotonicity Hypertonicity A solution having higher osmotic pressure than the body fluids (0.9% Nacl ) is known as hypertonic solution. These solutions draw water from the body tissues to dilute and establish equilibrium.

41. ISOTONICITY Solutions that have the same osmotic pressure as that of body fluids are said to be isotonic with the body fluid. Body fluids such as blood and tears have osmotic pressure corresponding to that of 0.9% Nacl or dextrose aqueous solution; thus, a 0.9% Nacl or 5 %, dextrose solution is called as isosmotic or isotonic For example, a 0.9% w/v solution of Nacl in water is considered to be isotonic in relation to RBC’s and their semi-permeable membranes Requirements of isotonic solutions are that they must not cause any contraction or swelling of the tissues

42. The product must not produce discomfort when installed in the eye, nasal tract, blood, or other body tissue. On addition of 0.9gm Nacl /100ml (0.9%) in to blood ( defibrinated ), the cells retain their normal size. Isotonic solution should be restricted to solutions having equal osmotic pressure with respect to a particular membrane. Hypo tonicity A solution with low osmotic pressure than body fluids is known as hypotonic solution. The effects of administering a hypotonic solution are generally more severe than with hypertonic solutions, since ruptured cells can never be repaired.

43. Hypertonic solutions show the opposite effect when compared to hypertonic solutions where the net movement of water into the cell causes them to swell Tonicity agents are substances which are used to maintain the isotonicity , so that the pain of injection is reduced. T hese substances should be compatible with other ingredients of the formulation Examples of tonicity agents are Sodium chloride, potassium chloride, dextrose, mannitol, sorbitol etc.

44. Methods of adjusting Tonicity and pH Sodium chloride equivalent method Tonicity equivalent or sodium chloride equivalent method is used to adjust the tonicity of pharmaceutical solutions. Sodium chloride equivalent (E) of a drug is the amount of sodium chloride that is equivalent to 1 gm of the drug. The percent of sodium chloride required for adjusting the isotonicity can be calculated using the following equation. PSA = 0.9 – (PSM x E of medicament) Where, PSM = Percent strength of medicament PSA = Percent of sodium chloride for adjustment of isotonicity

45. Above equation is used to calculate the amount of adjusting substance (sodium chloride) required for making the solution isotonic. It is valid for 100 ml solution. Example - Calculate the gram of sodium chloride needed to make 30 ml of a 2% isotonic physostigmine salicilate solution using sodium chloride method. Solution: E value of physostigmine salicilate = 0.16 PSM =2.0 % Volume of preparation required = 30 ml For equation PSM = 0.9 – (PSM x E of medicament) = 0.9 – (2.0 x 0.16) = 0.9 - 0.32 = 0.58 %

46. The above strength is valid for 100 ml since is expressed in percent. It should be prepared from 30 ml of solution For 100 ml of solution, sodium chloride required = 0.58 For 30 ml of solution, sodium chloride required =? 30x 0.58/100 = 17.4/100 =0.174 g of sodium chloride g)Suspending agents They are excipients which are added to the formulation in order to improve the stability of the formulation by preventing the sedimentation of the particles. They are mostly used in injectable suspensions. Gelatin and PVP are some examples

47. h)Emulsifying agents Emulsifying agents are added to injectable emulsions in order to increase the stability of the formulation. They are used to prevent separation of two phases. Examples of emulsifying agents are soap, SLS etc. i )Chelating agents They are substances which act on metals which catalyze degradation and inactivate them. Examples are EDTA, disodium edetate , tetra sodium edetate etc.

48. j) Co-Solvents Co-solvents are solvents which are added in smaller quantity to the formulation to enhance the solvent power of the primary solvent. Examples of co-solvents are Ethanol, PEG, glycerin etc.