Parenteral products

Parenteral products

1. PARENTERAL PRODUCTS RESHMA FATHIMA K | ASSISTANT PROFESSOR | GRACE COLLEGE OF PHARMACY, PALAKKAD

2. Parenteral ( Gk , para enteron , beside the intestine) dosage forms differ from all other drug dosage forms, because they are injected directly into body tissue through the primary protective systems of the human body, the skin, and mucous membranes. They must be exceptionally pure and free from physical, chemical, and biological contaminants. These requirements place a heavy responsibility on the pharmaceutical industry to practice current good manufacturing practices ( cGMPs ) in the manufacture of parenteral dosage forms and on pharmacists and other health care professionals to practice good aseptic practices (GAPs) in dispensing parenteral dosage forms for administration to patients

3. Certain pharmaceutical agents, particularly peptides, proteins, and many chemotherapeutic agents, can only be given parenterally , because they are inactivated in the gastrointestinal tract when given by mouth. Parenterally -administered drugs are relatively unstable and generally highly potent drugs that require strict control of administration to the patient. Due to the advent of biotechnology, parenteral products have grown in number and usage around the world.

4. Characteristics of parenteral dosage forms Parenteral products are unique from any other type of pharmaceutical dosage form for the following reasons: All products must be sterile. All products must be free from pyrogenic (endotoxin) contamination. Injectable solutions must be free from visible particulate matter. This includes reconstituted sterile powders. Products should be isotonic, although strictness of isotonicity depends on the route of administration. Products administered into the cerebrospinal fluid must be isotonic.

5. Ophthalmic products, although not parenteral, must also be isotonic. Products to be administered by bolus injection by routes other than intravenous (IV) should be isotonic, or at least very close to isotonicity . IV infusions must be isotonic . All products must be stable, not only chemically and physically like all other dosage forms, but also ‘stable’ microbiologically (i.e., sterility, freedom from pyrogenic and visible particulate contamination must be maintained throughout the shelf life of the product). Products must be compatible, if applicable, with IV diluents, delivery systems, and other drug products co-administered Characteristics of parenteral dosage forms

6. Advantages of Parenteral Administration Useful for patients who cannot take drugs orally Rapid onset of action Useful for emergency situations Providing sustained drug delivery (implants, im depot inj ) Avoid first pass metabolism Can inject drug directly in to a tissue (target drug delivery) Useful for delivering fluids, electrolytes, or nutrients (TPN) Can be done in hospitals, ambulatory infusion centers and home health care centers Complete bioavailability.

7. DISAdvantages of Parenteral Administration Pain on injection Difficult to reverse an administered drug’s effect. Sensitivity or allergic reaction at the site of injection. Requires strict control of sterility & non pyrogenicity than other formulation . Trained person is required. Require specialized equipment, devices, and techniques to prepare and administer drugs. More expensive and costly to produce.

8. The term parenteral literally means to avoid the GIT (gastrointestinal tract) and refers to any route of administration outside of or beside the alimentary tract. Thus, parenterals are injectable drugs that enter the body directly and are not required to be absorbed in the gastrointestinal tract before they show their effect. Parenteral routes of administration usually have a more rapid onset of action than other routes of administration. PARENTERAL ROUTES

9. PARENTERAL ROUTES

10. Preformulation Factors Preformulation is the study of physical and chemical properties of drug/ excipients prior to formulation. Before going for manufacture of parenterals some properties of raw materials must be studied. COLOR Color is a property of inherent chemical structure of drug which indicates intensity or level of unsaturation. Color intensity depends on the extent of conjugated unsaturation, also the presence of chromophores such as –CO, -NO2, -NH2. Certain saturated compounds also exhibit color due to minute traces of highly unsaturated, intensity colored impurities and/ degradation products.

11. During highly stressed conditions of heat, light and oxygen, most of these compounds tend to produce color. A change in color suggest the primary idea about chemical instability of the product. MOLECULAR STRUCTURE AND WEIGHT Molecular structure and weight are the basic characteristics of the drug which must be determined. Any small change in the molecular structure can significantly change the properties of the compound. That change indicates the chemical instability of that material. If such material is used for the manufacture of parenteral it may deteriorate the quality of the product.

12. Particle size and shape are generally determined by using scanning electron microscope . For the purpose of comparing with the future batches, the morphological characteristics of the drug substances should be recorded accurately by a photomicrograph. Polarized lights are refracted by crystalline materials and are thus visible when polarization attachments in the ocular and objectives are crossed at a 90 angle, whereas amorphous or glossy substances become invisible. These studies give the information about crystal structure or the amorphous nature of the substance. Changes in the crystal structure causes changes in the properties like solubility behavior, pka etc. so it becomes necessary to study particle size and shape in order to know whether any polymorph exist in the sample or not. Particle size and shape

13. Thermal Analytical Profile Samples may have been exposed to changes in temperature environment during synthesis and isolation which may be exhibited as a thermal profile, when the sample is heated between ambient temperature and its melting point. The sample will neither absorb nor give off heat prior to its melting point, if no thermal history exists for the compound. The basic technique used to study this phenomenon is called differential thermal analysis (DTA). Melting or fusion, crystalline structure changes such as polymorphic transitions, boiling, sublimation and desolvation are certain examples of characteristic endothermic transitions that can be detected by this technique. DSC is a similar process. Thermo gravimetric analysis (TGA) is also a thermal analytical method used to detect the existence and stability of solvated drug molecules.

14. Solubility For the development of parenteral product, solubility is of prime importance. In general solubility is a function of chemical structure, salts of acids or bases represent the class of drugs having the best chance of attaining the degree of desired water solubility. According to the drug moiety the analytical method used for measuring solubility may vary. If unsaturated conjugation is present in the drug structure, enabling it to absorb visible or uv light, spectrophotometric analysis can be performed. Determination of solubility of compounds that donot absorb uv or visible light can be attempted by transferring filtered aliquot solutions on to previously tared weighing pans, evaporating the solvent, and drying to constant weight under low temperature conditions.

15. Ionization constant From the ionization constant, the pH dependent solubility of a compound can be determined. Potentiometric pH titration or pH solubility analysis is used for determination of pka . The degree of ionization of an acid or base is determined by the ionization constant of the compound. Specially pH dependent solubility estimation is important in case of large volume parenterals which exhibits certain limitations of pH while administering into the body.

16. PARTITION COEFFICIENT The partition coefficient P is a measure of lipophilicity of a compound. Partition coefficient can be measured by determining the equilibrium concentration of a drug in aqueous phase and oil phase held in contact with each other at a constant temperature. It can be expressed as P = [C oil]/ [C water]

17. General requirements for parenteral dosage forms The finished parenteral product must possess following properties Stability The stability of parenteral preparation is very important. The physical as well as chemical stability of parenteral preparation must be maintained during storage as these products directly enter into the blood. The byproduct of instability may be harmful to body or it may affect the solubility of the product.

18. Sterility The parenteral preparations should be free from micro-organisms. Aseptic conditions are required to be maintained during the preparation of parenteral products and its administration. Free from pyrogens The parenteral preparations should be free from toxin and pyrogens . The parenteral product undergoes the pyrogen testing. These pyrogens are byproducts of microbial metabolism causing rise in body temperature.

19. Free from foreign particles The parenteral product should be free from foreign particles such as dust and fibres . To ensure this the parenteral products must pass the clarity test. Isotonicity The parenteral preparations should be isotonic with the blood plasma and body fluids. It is very important in order to avoid any complications (pain at site of injection, rupture or swelling of RBCs) after administration of parenteral products.

20. Specific gravity The parenteral products meant for intra-spinal injections should have the same specific gravity as that of spinal fluid into which the same are to be injected. Chemical purity The parenteral products should be free from chemical purities or it should be within certain limit as specified in the monograph of that preparation in the pharmacopoeia.

21. VEHICLES The medicaments are dissolved in these vehicles. Vehicles can be categorized into two categories aqueous and non – aqueous vehicles. AQUEOUS VEHICLE The pyrogen test or bacterial endotoxin test were performed for vehicles for aqueous injections. Generally water for injection is used as vehicle, unless otherwise specified in the individual monograph. Aqueos vehicles used for the purpose of formulation of small volume parenterals are:

22. Water for Injection (WFI), USP Water for injection is highly purified water which is subsequently sterilized and used as vehicle for the purpose of injectable preparation. The pH of water for injection is 5.0 to 7.0. the USP requirement is not more than 10 parts per million of total solids . Reverse osmosis or distillation is used for the preparation of WFI. It is stored in chemically resistant tank for less than 24 hrs at room temperature or for a longer period at specific temperature. It should not contain any added substances. It should meet USP pyrogen test.

23. b) Bacteriostatic water for injection (BMFI) Bacteriostatic water for injection is used for making parenteral solutions which are prepared under aseptic conditions and not terminally sterilized. It may contain any bacteriostatic agents when filled in containers of 30ml or less. It should meet USP sterility test. c) Sterile water for Injection (SWFI), USP This is also known as sterile water for irrigation. It is used for washing wounds, surgical incisions or body tissues. Multiple dose containers not exceeding 30ml are mostly used for this. It contains or more suitable bacteriostatic agents.

24. Non- Aqueous vehicle Sometimes it becomes necessary to use vehicle other than water or in addition to water mainly because of solubility problems or hydrolytic reactions. Non- aqueous vehicles used for the purpose of formulation of parenteral are of two types: water miscible and water immiscible. The water miscible vehicles used are glycerin, polyethylene glycols, propylene glycols, alcohol. Examples of water immiscible vehicles are corn oil, cotton seed oil, peanut oil, sesame oil etc. the non- aqueous vehicles used must possess some properties like they should be non-irritant, non-toxic, or non-sensitizing and it should not exert any undesirable effect in the formulation ingredients. Additionally it should be safe in the volume of administration, and also provided they do not interfere with the therapeutic efficacy of the preparation or with its response to prescribed assays and tests.

25. ADDITIVES They are suitable substances which may be added to the preparations intended for injections to improve the quality or stability, unless prescribed in the individual monograph. Additives should be use only if it is necessary to use them. Selected additives must be compatible with drug physically and chemically. The quantity of these agents must be as possible as minimum. Anti microbial Agents Substances that kill or inhibit the growth of micro-organisms are termed as antimicrobials. Antimicrobials are mostly classified acc to the microorganisms they are effective against or chemical groups present in their structure. Antimicrobial agents added in the multi-dose or single dose parenteral preparations (mostly if they are sterilized by filtration method). Therefore, the lowest level at which it is effective is determined so that the efficacy can be maintained throughout the shelf life of the product.

26. Phenol, benzethonium chloride, benzyl alcohol and chlorobutanol are certain examples of antimicrobial agents. BUFFERING AGENTS These agents are added to maintain the pH of the formulation within the pharmacopoeial limit. Maintaintanace of the pH is very important for avoiding irritations that may be produced if pH is not maintained properly. Maintainance of pH is also necessary for some drugs which are having stability problems with different pH values. Some of the commonly used buffering agents are sodium hydroxide, citrates, phosphates. Etc.

27. ANTI OXIDANTS They are substances which improve the stability of the preparation by delaying the oxidation of the API and other excipients present in the formulation. Examples of such anti oxidants are ascorbic acid and sodium bisulfate etc. Anti oxidants are classified into three groups: 1.True antioxidants They inhibit oxidation by reacting with free radicals and blocking chain reactions.

28. 2.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. 3.Anti oxidant synergists : they have less anti oxidant property themselves, but they enhance the antioxidant property of the first group by reacting with the heavy metal, ions that catalyze oxidation.

29. Tonicity modifiers The parenteral products must be isotonic with blood plasma or other body fluids. Tonicity modifiers added to make the solutions isotonic. This reduces the irritation at the site of injection (in case of small volume parenterals) and diminishes the effect of administration of large volume of fluids on RBCs. These agents must be compatible with all ingredient of formulation. Examples of tonicity agents are sodium chloride, potassium chloride, dextrose, mannitol, sorbitol etc.

30. 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. 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.

31. Chelating Agents These agents forms the complexes (chelate) with metal ions and increases their dissolution. They also act on metals which catalyze degradation and inactive them. Examples is EDTA, disodium edetate, tetra sodium edetate. Solubilizing Agents These agents used to increase the solubility of the drugs which are slightly soluble in water. The solubility of drug can be increased by addition of surfactants or the co solvents. Examples of co-solvents are ethanol, PEG, glycerine etc. examples of surfactants are tweens, polysorbates etc.

32. ISOTONICITY AND ITS IMPORTANCE For a solution to be termed as isotonic (equal tone) it must have the same osmotic pressure (more specifically tonicity) as that of specific body fluid (blood plasma or any specific fluid). It is important for a parenteral solution to be isotonic with a body fluid to prevent irritation and cell damage, and to maximize drug efficacy. In such solutions RBCs neither shrink nor swell means they maintain their tone, therefore they are referred to as isotonic solutions. The osmotic pressure of solution is maintained by the addition of tonicity modifiers. Examples such agents are sodium chloride, potassium chloride, dextrose, mannitol, sorbitol etc.

33. Blood plasma contains 0.88% of inorganic salts mainly sodium chloride which makes the main contribution to the osmotic pressure of blood. A solution containing 0.9% of sodium chloride is therefore, practically isotonic with blood plasma and considered as standard. Significance of Isotonicity If a hypotonic solution (with lower osmotic pressure than that of a body fluid) is administered intravenously water will pass into the red blood cells, causing them to swell and possibly burst (hemolysis) If a hypertonic solution (with higher osmotic pressure than that of a body fluid) is administered intravenously then water is drawn from the cells in an attempt to dilute the solution, causing them to shrink ( crenation)

34. For IV administration solution must be isotonic as it is directly enter into blood. For subcutaneous it is not must, for intramuscular injection solution should be slightly hypertonic to increase absorption. Intrathecal solutions are also required isotonic. Because that are injected in CSF so change in osmotic pressure may cause vomiting and other side effects. The diagnostic solutions must be isotonic to avoid any false reactions. Nasal drops should be isotonic with plasma, eye drops should isotonic with lachrymal fluid to avoid irritation of eyes.

35. PRODUCTION OF PARENTERAL PRODUCTS Production of parenteral products is different from production of other pharmaceuticals. The guidelines regarding the entry of microorganisms and impurities are more stringent as compared to non-sterile dosage forms. The general procedure for manufacture of parenterals includes following points. Cleaning and Washing of containers and closures. Soak the containers in detergent solution for nearly 12 hours. This removes the sticking particles and greasy materials after this the containers are wash with tap water to three to four times till detergent solution is completely removed.

36. Containers are treated with 1.0% hydrochloric acid (this removes surface alkalinity) and wash again with tap water. Rinse with de-ionized water and finally with distilled water and subjected to sterilization for 4 hours at 200 C. Rubber closures are boiled with 1.0 % detergent solution for 30 minutes and wash it with tap water till free from detergent. Boil for 30 minutes using 1% HCl solution and wash with tap water. Boil with 1.0% sodium carbonate and wash again. Treat them with double strength bacteriostatic solution. Wash three to four times with pyrogen free water. Sterilize by autoclave at 115 C for 30 minutes.

37. Preparation of solution Dissolve the API in water for inj with const stirring. After completely dissolving the drug other excipients are added one by one and stirred until dissolved. The pH is adjusted to the required range by using buffering agents like sodium hydroxide and hydrochloric acid. Make up the volume and mix with water for injection. The pH is again adjusted if necessary. STERILIZATION Sterilization is defined as a process of removal or killing of microorganisms present in object by using various methods. Sterilization can be achieved by applying chemicals, heat, irradiation, high pressure and filtration.

38. Processing of sterile products Processing of sterile products can be performed in three ways. They are as follows: Terminal sterilization Sterilization by filtration Aseptic preparation

39. Terminal sterilization It mainly involves preparation, filling and sterilization. It includes usual filling and sealing of product containers under highly controlled environmental conditions. The microbial and particulate content of the in- process product is minimized and also it ensures the sterility of the product. Finally the product is sterilized by heat or irradiation sterilization process in its final container to ensure sterility.

40. Sterilization by filtration In sterilization by filtration containers are sterilized before filling of product. Here filter having a pore size of about 0.22µm or less is used for the purpose of filtration. Second filtration or double filtration is possible. By filtration sterilization, it is possible to remove bacteria and moulds but virus and mycoplasms are not essentially removed.

41. Aseptic preparation Aseptic technique refers to the procedure in which entry of microorganisms in to the product is strictly avoided. All the possible precautions should be taken to avoid the entry of microorganism along with the particulate matter and other impurities. All the required materials and container closure are sterilized separately and then brought together in an aseptic process. Here the sterilization of product in its final container is avoided. So it is critical that containers should be filled and sealed in an extremely high quality environment. The individual parts of the final product are generally subjected to various sterilization processes before aseptic assembly into a final product .

42. Filling Packaging and Labelling After sterilization procedure the solution is then filled into suitable containers. Bulk preparations are subdivided into unit dose containers during filling. This process forces a measured volume of the preparation through the orifices of a delivery tube designed to enter the constricted opening of a container by means of gravity, vacum or with the aid of a pressure pump . After filling, the containers are sealed which will retain the contents of the sterile product and will assure a tamper proof presentation. When a parenteral preparation is liable to deterioration due to oxidation, the operation of filling may be performed in an atmosphere of suitable inert gas like nitrogen, whereby the air in the container is replaced with this gas.

43. The content of the label includes Name of the preparation If liquid preparation, amount of drug in a specified volume or percentage drug content In the case of a dry preparation, the amount of active ingredient The route of administration The storage conditions and other instructions The expiration date The name and place of business of the manufacturer, packer. Manufacturing license number Identifying batch number The complete manufacturing history of the specific package, including all manufacturing, filling, sterilizing and labeling operations can be determined from the batch number

44. FORMULATION OF INJECTIONS Vehicles Additives 1. Solubilizing agents 2. Stabilizers 3. Buffering agents 4. A ntibacterial agents 5. Chelating agents 6. Suspending / emulsifying agents 7. Tonicity factors (modifiers)

45. Sterile Powders Sterile drugs become unstable in presence of water such drugs are provided in the dry form. These powders need to be dissolved in water before administration. Examples of such drugs are ceftriaxone, cefatoxim etc. Sterile water for inj is supplied with dry powders to reconstitute a solutions/ suspensions for administration. Such solutions meet all the criteria required for a sterile parenteral solution. Methods of preparing a sterile drug powder Sterile recrystallization Lyophilization Spray drying

46. Sterile recrystallization The drug is dissolved in a solvent and the obtained solution is sterilized through 0.22 micrometer membrane filter. A sterile anti-solvent is then added to crystalize the drug particles, which is filtered and dried aseptically. Advantages : This method is flexible and economic Process does not involve heating so heat sensitive drugs can be processed through this method.

47. Disadvantages This method can develop batch to batch variations Due to involvement of number of processes chances of contamination are more

48. LYOPHILIZATION It is a process of separating a solid substance from solution by freezing the solvent and evaporating the ice under vacuum. Drug solution is sterile filtered into sterile trays which are aseptically loaded into a freeze dryer. The solution is then frozen at -50 C and then dried by vacuum to separate the drug powder Advantage Removal of water at low temperature Process does not involve heating so heat sensitive drugs can be processed through this method.

49. Disadvantage Biological molecules are damaged by the stress associated with freezing and drying. It is costly and time consuming. Spray drying The solution of the drug is sprayed into a dry chamber where it comes in contact with a hot steam of a sterile gas having temperature about 80- 100 C. Advantage: it is simple, economical, scalable and faster method Disadvantage: it is not suitable for heat sensitive drugs.

50. Disadvantage: loss of drug during processing is more as compared to freeze drying. Limited solvent choice for a given drug. Cannot prepare product directly in vials or plates. Procedure for reconstitution Clean the rubber diaphragm of the medication vial and the diluent vial with a alcohol swab. Unpack the desired syringe, pull the plunger to fill the barrel with air equal to the desired amount of diluent.

51. Inject the air into the vial of WFI to create positive pressure and to ease withdrawal. Invert vial and withdraw the desired amount of WFI. Inject the WFI into the medication vial and withdraw the syringe and needle. Invert and shake the vial to mix well. Positive pressure may be created in the freshly mixed medication vial for easy withdrawal.

52. LYOPHILIZED PRODUCTS Lyophilization or freeze drying is a process in which water is frozen, followed by its removal from the sample, initially by sublimation (primary drying) and then by desorption (secondary drying). Freeze drying is a process of drying in which water is sublimed from the product after it is frozen . It is a drying process applicable to manufacture of certain pharmaceuticals and biologicals that are thermolabile or otherwise unstable in aqueous solutions for prolonged storage periods, but that are stable in the dry state. The term “ lyophilization ” describes a process to produce a pro duct that “loves the dry state Lyophilization is the most common method for manufacturing parenterals when aqueous solution stability is an issue

53. Freeze drying has been used in a number of applications for many years , most commonly in the food and pharmaceutical industries . PROCESSING There are four stages in the complete drying process: Pretreatment Freezing Primary drying Secondary drying

54. Freeze-drying process Freeze drying is mainly used to remove the water from sensitive products, mostly of biological origin, without damaging them, so they can be preserved easily, in a permanently storable state and be reconstituted simply by adding water . Examples of freeze dried products are: antibiotics, bacteria, sera, vaccines, diagnostic medications, protein containing and biotechnological products, cells and tissues, and chemicals . The product to be dried is frozen under atmospheric pressure. Then, in an initial drying phase referred to as primary drying, the water (in form of ice) is removed by sublimation; in the second phase, called secondary drying, it is removed by desorption. Freeze drying is carried out under vacuum .

55. Pretreatment Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation revision (i.e., addition of components to increase stability and/or improve processing), decreasing a high vapor pressure solvent or increasing the surface area. In many instances the decision to pretreat a product is based on theoretical knowledge of freeze-drying and its requirements, or is demanded by cycle time or product quality considerations . Methods of pretreatment include: Freeze concentration, Solution phase concentration, Formulation to Preserve Product Appearance, Formulation to Stabilize Reactive Products, Formulation to Increase the Surface Area, and Decreasing High Vapor Pressure Solvents. Traditionally , lyophilization cycle design has been divided into three parts

56. Freezing , in which the liquid sample is cooled until pure crystalline ice forms from part of the liquid and the remainder of the sample is freeze-concentrated into a glassy state where the viscosity is too high to allow further crystallization. Primary drying, wherein the ice formed during the freezing is removed by sublimation under vacuum at low temperatures , leaving a highly porous structure in the remaining amorphous solute that is typically 30% water. This step is carried out at pressures of 10-4 to 10-5 atmospheres, and a product temperature of –45 to –20°C; Sublimation during primary drying is the result of coupled heat- and mass-transfer processes. Secondary drying, wherein most of the remaining water is desorbed from the glass as the temperature of the sample is gradually increased while maintaining low pressures.

57. APPLICATIONS Pharmaceutical and biotechnology Pharmaceutical companies often use freeze-drying to increase the shelf life of products, such as vaccines and other injectables . By removing the water from the material and sealing the material in a vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection Food Industry Freeze-drying is used to preserve food and make it very lightweight. The process has been popularized in the forms of freeze-dried ice cream, an example of astronaut food