LARGE VOLUME PARENTERALS FORMULATION.pptx

PHYSIOLOGICAL AND FORMULATION CONSIDERATION OF PARENTERALS
MANUFACTURING AND EVALUATION OF LARGE VOLUME PARENTERALS

1. WELCOME 1

2. PHYSIOLOGICAL AND FORMULATION CONSIDERATION, MANUFACTURING AND EVALUATION OF LARGE VOLUME PARENTERALS PRESENTED BY : LANIYA NASRIN K FIRST SEMESTER M PHARM DEPARTMENT OF PHARMACEUTICS FACULTY IN-CHARGE : Dr. PRASANTH M S ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACEUTICS 2 GOVERNMENT MEDICAL COLLEGE, THIRUVANANTHAPURAM

3. INTRODUCTION TO LARGE VOLUME PARENTERALS 01 02 03 05 04 CONTENTS PHYSIOLOGICAL AND FORMULATION CONSIDERATIONS MANUFACTURING OF LVPs REFERENCES EVALUATION OF PARENTERALS 3

4. 01 INTRODUCTION TO LARGE VOLUME PARENTERALS 4

5. PARENTERAL PARA OUTSIDE ENTERON INTESTINE It is a sterile preparations containing one or more active ingredients intended for administration by injection, infusion or implantation into the body. 5

6. LARGE VOLUME PARENTERALS (LVPs) Aqueous solutions usually supplied in volume of 100 mL to 5000 mL OR A single-dose injection that is intended for intravenous use and is packed in container labelled as containing more than 100 mL Common sizes are : 250, 500,1000, 3000 and 5000 mL Generally packed in glass or flexible containers Mainly used for fluid replacement therapy . 6

7. 7

8. 8

9. 1.ELECTROLYTE SOLUTION It is used when the electrolyte or acid-base balance of blood changes. Na ⁺ To provide osmotic pressure K⁺ Provide acid-base balance Ca²⁺ In blood clotting and secretion of hormones Cl⁻ & HCO₃⁻ In providing acid – base balance Sodium chloride 0.9 % Lactated ringer’s injection Lactated ringer’s injection with 5%w/v dextrose Multiple electrolyte solution Multiple electrolyte solution with 5%w/v dextrose 9

10. 2.NUTRITIONAL SOLUTION Nutritional solutions are mainly as Partial Parenteral Nutrition (PPN) and Total Parenteral Nutrition (TPN) TOTAL PARENTERAL NUTRITION (TPN) PARTIAL PARENTERAL NUTRITIONS (PPN) 10

11. 3. CARBOHYDRATES SOLUTION It is generally administered to hospital patients. The standard solution are 50% dextrose /D50 and 10% invert sugar. These solutions are hyper osmolar Infused through large central veins. It is infused in combination with amino acid. 11

12. 4.HYPER ALIMENTATION SOLUTION 5. CARDIOPLEGIC SOLUTION Administration of large volume of nutrients to the patients who unable to in-take food orally for more than several weeks. Used in heart surgery. To prevent injury to myocardium during reperfusion. To minimize reperfusion injury resulting from tissue edema. CONTENT CONTENT SOURCES Calories Dextrose Nitrogen Crystalline amino acid Electrolytes Na⁺,K⁺,Cl⁻ & PO₄⁻ Vitamins Water & fat-soluble Minerals Traces of Zn,Cu,Mn,Cr… 12

13. 6. PERITONEAL DIALYSIS SOLUTION 7. IRRIGATING SOLUTION Infused continuously into abdominal cavity, peritoneum and then continuously withdrawn. Remove toxic substance from body Aid and accelerate excretion normal Treat acute renal insufficiency Intended to irrigate, flush and aid in cleansing body cavities and wounds NS used as irrigating solution 13

14. 14

15. PHYSIOLOGICAL AND FORMULATION CONSIDERATIONS 02 15

16. 16

17. 1.PHYSIOLOGICAL CONSIDERATION 1.A-pH consideration For maximum physiological acceptability, the target pH is 7.4 In IV route --- wide range can be tolerated and rapid dilution with blood achieved In IM route --- 2-12 range can be tolerated and slower dilution rate Tolerability depends on its buffering capacity. APPROVED BUFFERS IN THE PARENTERAL PRODUCTS BUFFER pH RANGE Acetate 3.8-5.8 Ammonium 8.25-10.25 Ascorbate 3.0-5.0 Benzoate 6.0-7.0 Citrate 2.1-6.2 Diethanolamine 8.0-10.0 17

18. 1.B-TONICITY CONSIDERATION All parenteral product should be isotonic osmolarities should target b/w 280-290 m Osmo/L during a formulation. For LVPs Isotonicity is very essential. Either the rapid dilution with blood that will occur after injection. To avoid the tissue damage parenteral formulations should be isotonic with human plasma . TONICITY ADJUSTMENT METHOD 18

19. 2.A-CHOICE OF EXCIPEINTS 2.B-PHARMACOKINETICS OF DRUGS In parenteral product the quality, particularly in microbial term of excipients should be considered The injectable grades are usually used for parenteral excipients It should have strict bio burden and endotoxin limit. Excipients of pharmacopeial grade also acceptable. The absorption rate for route of administration, distribution, metabolism and excretion of drug have effect based on formulation. There may be need of modified or sustained released formulation. 2.FORMULATON CONSIDERATION 19

20. 2.C-DRUG SOLUBILITY 2.D- DRUG STABILITY The solubility of a substance at a given temperature is the concentration of the dissolved solute in a saturated solution. The formulation must contain co-solvents which sufficiently increase and maintains the drug in the solution. To enhance solubility of drug -solubilizers such as surfactants and complexing agents used Stability determine the storage condition and drug expiring date If the drug posses significant degradation problems in the solution ,then freeze dried or sterile solid dosage form should be developed. All parenteral are required to be stable under predetermined manufacturing, storage and usage conditions Sterile dosage forms need to maintain chemical and physical stability throughout its shelf-life 20

21. 2.E-DRUG-EXCIPIENT COMPATIBILITY 2.F-SUITABLE CONTAINERS The main challenge of all parenteral is to achieve a good compatibility of drug substance with excipients No formation of new impurities either by degradation of the drug substance Formation of new chemical entity between drug substance and excipient. The compatibility of preparation with primary container (Leachable/adsorption to containers) is always a prime concern Plasticizers used to keep plastic flexible may lead to leaching as it may interact with some drug and solution Suitable containers must be selected which protect the product, allow inspection of the content, permit shipping and storage and convenient for clinical use 21

22. MANUFACTURING OF LARGE VOLUME PARENTERALS 03 22

23. LAYOUT OF PARENTRAL PROCESSING STORAGE AREA CONTROLLED CLEAN ENVIRONMENT ASEPTIC AREA CLEAN AREA QUARANTINE AREA INGREDINTS COMPONDING VEHICLES OF PRODUCT FILTRATION SOLUTES PROCESSING CLEANING STERILISATION EQUIPMENTS CONTAINER CLEANING STERILISATION COMPONENT FILLING SEALING PACKAGING PRODUCT STORAGE 23

24. PRODUCTION FACILITIES CLEAN AREA A clean environment designed to reduce the contamination of process and material It should withstand moisture, steam and detergents PREPARATION AREA The product is formulated More stringent control ASEPTIC AREA maximum control of microbial and particulate matters strict control measures Filling and sealing done here QUARANTINE AREA In process batches and approved batches stored separately FINISHING AND PACKAGING AREA Batches are packed and labelled Parenteral packing vital role in production of sterile preparation 24

25. MECHANICAL AREA: Unclassified GENERAL AREA: Unclassified CLEAN AREA: class100000, grade D, ISO 8 ASEPTIC ADJACENT AREA: class1000-10000, grade C, ISO 6-9 ASEPTIC AREA: class100, grade A/B, ISO 5 Movement of equipment and materials during filling, stoppering and capping Movement of equipment's and materials after process completed STERILE MANUFACTURING FACILITY 25

26. PRODUCTION PROCEDURE OF LVPs 26

27. 27

28. 1.VEHICLE AQUEOUS VEHICLE WATER MONOGRAPH IN THE USP WATER TYPE PREPARATION METHOD LIMIT FOR ENDOTOXIN FEATURE WATER FOR INJECTION (WFI) DISTILLATON ION EXCHANGE 0.25 EU/mL USED WITHIN 24 HOURS, STORE ABOVE 80 °C OR BELOW 5°C STERILE WFI DISTILLATION REVERSE OSMOSIS 0.25 EU/mL SINGLE DOSE CONTAINER,TO RECONSTITUTE STERILE SOLIDS AND DILUTE STERILE SOLUTIONS BACTERIOSTATIC WFI DISTILLATION REVERSE OSMOSIS 0.5 EU/mL MULTIPLE AND SINGLE DOSE PRODUCTS 28

29. CITY WATER SAND FILTER PRIMARY SOFTNER DECHLORINATOR POLISHER (SECONADARY SOFTNER) REVERSE OSMOSIS STORAGE TANKS MULTIPLE EFFECT STILL CLEAN STEAM GENERATOR COOL LOOP HOT LOOP WFI SYSTEM 29

30. OPERATION ON WATER USE Prefiltration To remove iron and any suspended matters. Activated carbon beds For removal of chlorine and organics. Water softening by ion-exchange To remove alkaline earth metals, calcium and magnesium thus minimize the formation of scale deposits De-chlorinator (sodium metabisulphite and carbon banks) To remove chlorine from water. Flocculating agent To remove suspending agent pH adjustment to 6.0-6.5 To reduce scale deposits. UV-radiation To suppress the microbial growth. 30

31. REVERSE OSMOSIS PRE-TREATMENT OF WATER The separation of solutes from water by applying pressure on more concentrated solution in contact with semi-permeable membrane to give less concentrated solution . Solutes may be charged(ions) or neutral (organics). CHARGED PARTICLES Excluded due to interfacial tension at the water membrane interface ORGANICS Excluded by sieve mechanism Higher the size or molecular weight efficiency of exclusion increases. 31

32. 32

33. DISTILLATION The continuous process of heating water to its boiling point in a confined environment so that the steam formed can be passed through a separator The action of purifying a liquid by a process of heating and cooling. The process of removal of impurities from the liquid by continuous heating above 100 °C and cooling simultaneously. This aid killing of microorganism. Phase change would leave all the impurities behind producing pure water vapour The vapour is condensed to liquid water Filtered and stored in a chemical resistant stainless steel tank at a cold temperature around 5°C or elevated temperature above 80°C to inhibit microbial growth and pyrogen formation. 33

34. DISTILLATION UNIT 34

35. STORAGE WATER PURITY Temperature kept constant at 80 °C or below 5°C USP permit to be stored at room temperature but for maximum 24 hours. QUALITY STANDARD FOR WFI QUALITY STANDARD HOW MEASURED SPECIFICATION Inorganic content Water conductivity at 25 °C < 1.3 µs/cm Organic content Total organic carbon <0.5 mg/L Pyrogen content LAL <0.25 EU/ml Microbial content Total bacterial count <10 CFU/10 ml 35

36. 2.EXCIPENTS / ADDITIVES ADDITIVES CHARACTERISTIC EXAMPLE ANTI-OXIDANT Prevent degradation of therapeutic agent due to oxidation Ascorbic acid, sodium bisulphite BUFFER To maintain pH thus result stability Ideal is 7.4 Acetate buffer, sodium citrate STABILIZERS Parenteral are prone to unstable, so used to stabilize the formulation Glycerin, sodium saccharin SOLUBILIZING AGENT Used to increase solubility Act as solubilizer emulsifiers & wetting agent Ethanol, PEG-300, polysorbate 20,40,80 TONICITY ADJUSTER To maintain tonicity with body fluids Glycerin, mannitol, dextrose, sorbitol PROTECTANT To prevent the loss of activity of therapeutic agents Sucrose, trehalose 36

37. STABILITY OF RAW MATERIALS The chemical nature of the materials are varied, so storage requirement and stability characteristics are different. Heat, light, moist and air can adversely affect materials over a period of time. Containers for the drug substance important factor to stability consideration Organic materials Sensitive to heat Natural fats and oils Double bond react with Oxygen to form peroxides Amino acids and proteins adversely affected by heat, light, air and moisture Hydrated substance Pickup moisture from environment Basic materials Absorb carbon dioxide from air 37

38. 3.CLEANING OF CONTAINERS AND EQUIPMENTS Equipment and containers are thoroughly cleaned with detergent and washing with →tap water →clean distilled water →WFI Rubber closures and glass bottles are cleaned in mechanical equipment which is heated electrically Detergent are mostly used for cleaning the rubber closures This rubber closures are washed first with water autoclave rinse second time with preservatives • Equipment's are mostly disassembled and each parts are thoroughly scrubbed and cleaned Two types of rinsers Rotary type rinser. Convey type rinser 38

39. 4.FILTRATION The separation of undissolved particles from a liquid by passing a solution through a septum/porous medium that allows the liquid to pass but retains the particles. 39

40. IDEAL FILTER 40

41. GENERALTYPES OF FILTERS BASED ON SIZE OF PORES IN MEMBRANE FILTER TYPE SIZE RANGE (µm) USED TO REMOVE PARTICLE 10-200 Pollen ,particles, some bacteria MICRO-FILTER 0.1-10 All bacteria, yeast, colloids ULTRA-FILTER 0.001-0.1 Most viruses, large organic compounds NANO-FILTER Less than 0.001 Small organic compounds, ions BASED ON BEHAVIOUR WITH WATER FILTER TYPE EXAMPLE HYDROPHOBIC Millex filter HYDROPHILIC Durapore hydrophilic cartridge filter 41

42. TYPES OF FILTRATION SCREEN FILTERATION(SURFACE FILTRATION) It is a screening action by which pores or holes of the medium prevent the passage of solids. Mechanism -straining and impingements. Plates with holes or woven sieves are used. 42

43. DEPTH FILTRATION CAKE FILTRATION The slurry penetrates to a point where the diameter of solid particles greater than that of the void or channel. Mechanism -entanglement It is extensively used for the removal of small amount of contaminants from relatively large volume of liquids. A filter consist of a coarse woven cloth which a concentrated suspension of rigid particles is passed so that they bridge the holes and form bed The particles will be held back, while liquid passes through the small interstices. 43

44. 44

45. DESTRUCTIVE TESTING To qualify the filter initially BACTERIAL RETENTION TEST The filter is challenged to known population of microorganism using conditions that simulate the actual process Conditions that simulated: 1.Filtration pressure and flow rate 2.Duration of filtration process 3.Temperature 4.Same filter type and configuration 45

46. PRODUCT–FILTER COMPATIBILITY & FILTER EXTRACTABLES It is performed by filter manufactures The filter manufacturers provide information on the flush volume required to yield –ve oxidizable substance Provide the data on the level of extractables obtained with different solvent exposure. Filter material must be compatible with the chemical nature of liquid being filtered. Potential filter extractables: oligomers , mold releasing agent, antioxidants, wetting agent, plasticizers, cartridge body and O-ring material 46

47. NON-DESTRUCTIVE TESTING Performed prior to and after using the filter in batch production IN PROCESS FILTER INTEGRITY TESTING Prior to actual filtration of the product, filter should be flushed either with product/ WFI to reduce potential extractables and downstream particles. Filter then subjected to filter integrity test ( Pre-filtration filter integrity test ) and after the solution is filtered, the filter is again subjected to 2 nd filter integrity test ( Post-Filtration filter integrity test ) 47

48. 48

49. BUBBLE POINT TEST The pressure at which bubbling occurs downstream of filter is called bubble point 49

50. P-minimum pressure when bubbling occurs d-pore diameter -contact angle between solid and liquid S-correction factor   .s   50

51. DIFFUSION TEST Q .k   Q-diffusion flow A-membrane surface area L-effective length -differential pressure -porosity K-diffusivity   51

52. PRESSURE DROP TEST WATER INTRUSION TEST It is applied to large surface area filters P-maximum allowed pressure drop D-rate of diffusion V-volume of system upstream t-time Patm- atmospheric pressure   To detect quality of hydrophobic filters   Intrusion(ml/min)   Water under pressure is forced to intrude into pore matrix Pressure drop from volume increases is converted into water flow rate 52

53. 5.CONTAINERS AND CLOSURES GLASS CONTAINERS Type-II glasses are generally employed. Glass IV bottles are packed with vacuum, sealed with a solid rubber closure and closure is held in place by aluminium band. Glass are both brittle and fragile Bottles must be withstand in internal and external pressure generated in autoclaving 53

54. PLASTIC CONTAINERS Available in different sizes-Most common 250, 500 and 1000ml Flexible LVP made of : 1.polyethylene 2.polypropylene 3.polyvinyl cellulose 4.polyamide 5.polycarbonate 6.Ethylene vinyl acetate 7.elastomers ADVANTAGES DISADVANTAGES Non-fragile Weight less Less storage space same drugs absorb plastics Some drugs and solutions leach a plasticizer out of the plastic, the plasticizer included to keep it flexible 54

55. RUBBER CLOSURES Design may range from the simple solid uniform stopper to a complex stopper containing holes, depression, wells and undercut’s. The most common rubber polymers used are natural and butyl rubber. Rubber permits entry of hypodermic needle into Injection vials and provide re-sealing of the vials after needle is withdrawn. 55

56. 6.FILLING High accurate filling are not necessary for LVPs, filling is generally uncomplicated 56

57. LIQUID FILLING VOLUMETRIC FILLING Employs pistons or peristaltic pumps High speed filling rates When product is sensitive, peristatic pump is used Filling accuracy with 0.5ml fill volume   Chase-logeman filling machine 57

58. TIME-PRESSURE FILLING NET-WEIGHT FILLING For sterile products A product tank connected to filling system that is equipped with pressure sensor Product flow occurs when tubing is mechanically unpinched and stops when tubing pinched Inova VFX M2428 model It uses piston and gravity fillers It doses the quantity of liquid being filled by measure of weight in dynamic condition VKPAK liquid filling machine 58

59. 7.SEALING The sealing operation, establishes the integrity of the container. The head space above fluid may be flushed with a gas (nitrogen/carbon dioxide) GLASS CONTAINERS The closure system of glass container consist of : 1.A rubber disk to maintain seal under high vacuum 2.An aluminium disk to provide additional security 3.An aluminium ring , which held both aluminium disk tightly against rubber stopper. SEMI-RIGID PLASTIC sealed with a rubber closure as primary seal with plastic over cap. 59

60. BLOW FILL SEAL (BFS) Accepted by US-FDA It takes only 10-15 seconds to produce one container. 60

61. FORM FILL SEAL(FFS) Similar to BFS ,this involve formation of large volume bags FORM formation of container FILL filling containers with content SEAL sealing of containers 61

62. 62

63. 8.STERILISATION Any process that effectively kill/eliminate transmissible agents from a surface, equipment, foods, medication or biological culture medium . 63

64. A.PHYSICAL METHOD A.1 THERMAL METHOD DRY HEAT STERILISATION MOIST HEAT STERILISATION It employ temperature range of: 180 for NLT 30 minutes, 170 for NLT 1 hour and for NLT 2 minutes. Mechanism of killing microorganism: Denaturation of protein and nucleic acid by oxidation Examples: 1.Hot air oven 2. Flaming 3.Red-hot sterilisation 4.Incineration Mechanism of killing microorganism: Denaturation and coagulation of protein molecules and cell constituents Examples: 1.Heating below 100 - Pasteurization & Inspissation 2.At 100 -Boiling & Tyndallisation 3.Heating above 100 - Autoclave DRY HEAT STERILISATION MOIST HEAT STERILISATION 64

65. A.2- RADIATION A.3-FILTRATION NON-IONIZING (hot sterilisation) 1.Infra-red rays 2.UV rays IONIZING(cold sterilisation) 1.gamma rays 2.X-rays Gamma rays causes ionization and free radical production UV light causes excitation UV having limited sterilisation power because of poor penetration in to most materials Gamma used mostly in industrial facilities It is used for heat sensitive materials It doesn't destroy microbes but removes the microorganism Mechanism : Sieving, Entrapment or Electrostatic attraction Filters: Membrane filters, Sintered, Seitz or Ceramic filters 65

66. B.CHEMICAL STERILISATION B.1-GASEOUS STERILISATION B.2-LIQUID STERILISATION It uses ethylene oxide and formaldehyde posses bactericidal activity Mechanism: alkylation of sulfhydryl, amino, hydroxyl and carboxyl group on proteins and amino acid of nucleic acid Ethylene oxide gas at temperature below 100 used, high efficiency with 100% result Formaldehyde low temperature method for sterilizing heat sensitive items.   It mainly uses: alcohol, phenols, aldehydes, halogens & hydrogen peroxides Hydrogen peroxide destroy wide range of microbes Phenols such as cresols, chlorhexidine or chlorxylenols Chlorine and iodine are sporicidal 66

67. 9. EVALUATION OF LARGE VOLUME PARENTERALS 67

68. 9.LABELLLING AND STORAGE The concentration of individual content should be clearly expressed. Storage condition must be mentioned. Contain adequate direction of use The label should bear an indication of the pH and osmolarity of the solution 68

69. GMP SCHUDULE-M PART 1A : specific requirement for manufacturing of sterile products, parenteral preparations(small volume injectables and large volume injectables) and sterile ophthalmic preparations 1.GENERAL- Very high degree precaution and prevention needed 2.BUILDING AND PREMISES- Standardized materials, water facility and aseptic area 3.AIR HANDLING- grade A(filling) , grade C (manufacturing) & RH of 55% rate 4.ENVIRONMENTAL MONITORING- Particulate monitoring of air, HEPA filter and air change 5.GARMENTS -clothing ,footwears and PPE 6.SANITATION 7.EQUIPMENTS 8.WATER AND STEAM SYSYTEM 9.STERILISATION 10.PRODUCT CONTAINERS AND CLOSURE 11.DOCUMENTATION 69

70. MANUFACTURING OF LVPs 70

71. EVALUATION OF PARENTERALS 04 71

72. 72

73. 1.LEAKER TEST Leaks can be due to incomplete and defective sealing, rubber-stoppering, pin-holes in packaging and improper storage conditions. Leak an cause: Loss of Product Product Decay Microbial Contamination Loss of Sterility Physico-chemical Contamination 73

74. DYE TEST 74 BUBBLE TEST

75. 2.CLARITY TEST / FOREIGN PARTICULATE MATTER TEST The parenteral preparation should be free from particulate matter of range 30-40 µm . VISUAL METHOD Entire product inspected under good light against black and white background Light background detect light particles and vice versa COULTER-COUNTER METHOD Increases in the resistance as particles approaches and passes through the orifices 75

76. 76 LIGHT-OBSCURATION PARTICULATE MATTER TESTING It uses a liquid particle-counter machine that is based on light scattering Beam of light (laser) is directed through a narrow capillary tube with a flowing stream of liquid. Any particle passing through the laser beam blocks a certain amount of light and casts across the photo-detector.

77. 3.PYROGEN TEST 3.A IN VIVO RABBIT TEST PRELIMINARY TEST /SHAM TEST 77

78. MAIN TEST 78

79. INTERPRETATION OF RESULTS NUMBER OF RABBIT INDIVIDUAL TEMPERATURE RISE ( °C) TEMPERATURE RISE IN THE GROUP ( °C) TEST 3 RABBIT 0.6 1.4 PASSES IF ABOVE NOT PASSES 3+5=8 RABBIT 0.6 3.7 PASSES 79

80. 3.B LAL TEST LIMULUS AMEOBOCYTE LYSATE / BACTERIAL ENDOTOXIN TESTS It is used to detect endotoxin from gram –ve bacteria Lysate obtained by lysis of amoebocyte of Horseshoe Crab—limulus Polyphemus . Lysate consist of pre-clotting enzymes and coagulogen 80

81. Measurement of opacity change Opacity ∝ concentration of endotoxin Measurement of color in which release of para –nitroanilide Para-nitroanilide is by-product of clotting reaction during LAL test Quantity of para-nitroanilide ∝ Conc. of endotoxin 81

82. 82 Due to prolonged usage of horseshoe crabs other methods have been developed Enzyme Linked Immunosorbent Assay Endotoxin is bound to a phage protein Detected by recombinant factor C (rFC) Quantified through detection of a fluorescence substrate Pyrogen stimulate monocytes to produce cytokines (IL-6 , TNF-a) or lead to formation of metabolites (Neopterin, nitrite) from cytokine-inducible pathway cells It can be measured in the supernatants of cultured cells by ELISA methods Test detect non-endotoxin and endotoxin pyrogen

83. 4.STERILITY TEST 4.A MEMBRANE FILTRATION METHOD 83

84. 4.B-DIRECT INOCULATION METHOD INTERPRETATION OF RESULTS If there is no visible evidence of microbial growth, interpreted as sample without intrinsic contamination product complies test for sterility 2. If microbial growth found product doesn’t complies and sterility test repeated 84

85. REFERENCES 06 Pharmaceutical dosage forms: parenteral medication-volume 1; Kenneth E Avis, Leon Lachman & Herbert A Liebermann; page no:13-37. Modern pharmaceutics,2 nd edition; volume 40 ;Gilbert S Banker & Christopher T Rhodes ;page no:493-499. Remington-essentials of pharmaceutics; Linda A Felton ; page no:495-515. An introduction to LVPs as pharmaceutical dosage forms and an E & L challenge – Dennis Jenke Large volume parenteral- https:ankders.Ankara.edu.com. Requirements and characteristics of large volume parenterals-product quality research institute- www.pqri.org 85

86. THANK YOU 86