Parenteral Product Administration Definition: Advantages disadvantages Route Compounds formulation drug:preformulation: yehicle:WFI Route Form Subcutaneous, Important added substances Intravenous Parenteral Products Intramuscular In what kind of Form Solution,Suspension,Emufsion Epidermal Dosage Forms Prep Dry powder,Liposome (aseptic filling) Xiaohui Wei Sterilization Method Injection formulations: xhwei@sjtu.edu.cn Route Form Method Selection Validation Sterility Testing: Quality Control Pyrogen Testing; GMP To build the Leaker Testing Sealing Verification; Quality into the Product Clarity and Particulate Testing 1.Introduction 1.Introduction Parenteral ÷Advantages. para(beside)+enteron(intestine)or not via the rapid onset;predictable effect;very high bioavailability;avoid individual digestive tract. difference; As a practical matter,the parenteral route encompasses injectable ÷Disadvantages: formulations.though implants are also included pain,discomfort,very hard to counteract an incorrect drug or dose. rectal administration would not fall under the definition of parenteral Special significant under the conditions: other non-oral dosage forms also are excluded (epicutaneous. 1.very inefficient or unreliable GIT absorption ocular,otic,nasal,pulmonary) 2.extensive mucosal or first-pass effect when oral; 3.Clinical need for rapid,assured high concentration; 1
1 Parenteral Parenteral Products Products Xiaohui Xiaohui Wei xhwei@sjtu.edu.cn Parenteral Parenteral Product In what kind of Form Administration Administration Route Solution, Suspension, Emulsion Dry powder, Liposome (aseptic filling) Compounds & formulation drug : preformulation; vehicle : WFI Important added substances Sterilization Method Injection formulations: Method Selection & Validation Quality Control Quality Control Sterility Testing; Pyrogen Testing; Leaker Testing & Sealing Verification; Clarity and Particulate Testing Dosage Forms & Prep Subcutaneous, Intravenous Intramuscular Epidermal Definition: Advantages & disadvantages GMP：To build the Quality into the Product Route & Form Route & Form 1. Introduction 1. Introduction Parenteral Parenteral : para (beside) + (beside) + enteron (intestine) or not via the (intestine) or not via the digestive tract. digestive tract. z As a practical matter, the As a practical matter, the parenteral parenteral route encompasses route encompasses injectable formulations, though implants are also included z rectal administration would not fall under the definition of would not fall under the definition of parenteral parenteral z other non-oral dosage forms also are excluded (epicutaneous epicutaneous, ocular, ocular, otic, nasal, pulmonary) 1. Introduction Introduction Advantages: Advantages: rapid onset; predictable effect; very high bioavailability; avoi rapid onset; predictable effect; very high bioavailability; avoid individual d individual difference; difference; Disadvantages: pain, discomfort, very hard to counteract an incorrect drug or dose. ug or dose. Special significant under the conditions: Special significant under the conditions: 1.very inefficient or unreliable GIT absorption ; 1.very inefficient or unreliable GIT absorption ; 2. extensive mucosal or first-pass effect when oral; 3. Clinical need for rapid, 3. Clinical need for rapid, assured high concentration; 1
Needle-free Injection Device 2.Routes of parenteral administration Primary Routes: Subcutaneous route:SC,SQ,Sq Intramuscular route:IM P IOLET BUBCTEUn Intravenous route:IV 品高密，n 。Other Routes: Intradermal,intra-arterial,intrathecal etc. Details please find: http://www.cdc.gov/nip/dev/jetinject.htm Skin Structure Free narvo Hair root For each route of administration, Smail blood describe 1.Where the drug is administered 2.Volume limitations Dermis 3.Formulation constraints Smooth muscle Adipoee tissue Sweat gland Nerve Receptors Copyngt 2001 Birjamn Cummng an iernt of Adsson Woily Longmir,ine 2
2 Needle-free Injection Device Details please find: http://www. cdc.gov/nip/dev/jetinject.htm 2. Routes of 2. Routes of parenteral parenteral administration administration Primary Routes: Primary Routes: Subcutaneous route: SC, SQ, Sq Intramuscular route: IM Intravenous route: IV Other Routes: Other Routes: Intradermal Intradermal, intra-arterial, arterial, intrathecal intrathecal etc. For each route of administration, describe 1.Where the drug is administered 2.Volume limitations 3. Formulation constraints Skin Structure 2
2.1.Subcutaneous Route Site:superficial fascia,5/8 inch ÷Volume:~2ml Characteristic:slower onset,less total abs. Formulation Constraints:not irritating Precautionary Notes: ensure that the needle is not in a vein. http://www.pharmacy.wsu.edu/courses/PharS531/Parenterals201.htm 2.2.Intramuscular Route 2.3.Intravenous Route Site:striated muscle fibers,1.5 inches Two types:IV injection and IV infusion needle or cannulation Volume:1~3ml,10ml sometimes ÷Characteristic: Type I IV injection(vein puncture) rapid onset: Site:large proximal veins drug depot,sustained-release; ÷Volume:1~100ml factors affecting the diffusion process control the release rate; Characteristic:extremely rapid and predictable response Formulation Constraints:nearly all drug classes Formulation Constraints: ÷Precautionary Notes: solutions and some emulsions potential muscular or neural damage ÷Precautionary Notes: Drug shock:too rapid abs.control the injection rate Thrombosis 3
3 http://www.pharmacy.wsu.edu/courses/PharS531/Parenterals20I.htm 2.1. Subcutaneous Route 2.1. Subcutaneous Route Site : superficial fascia, 5/8 inch Volume : ~2ml Characteristic Characteristic : slower onset, less total abs. slower onset, less total abs. Formulation Constraints : not irritating Precautionary Notes : Precautionary Notes : ensure that the needle is not in a vein. ensure that the needle is not in a vein. 2.2. Intramuscular Route 2.2. Intramuscular Route Site : striated muscle fibers, 1.5 inches striated muscle fibers, 1.5 inches Volume : 1~3ml, 10ml sometimes Characteristic : rapid onset; rapid onset; drug depot, sustained-release; release; factors affecting the diffusion process control the re factors affecting the diffusion process control the release rate; lease rate; Formulation Constraints Formulation Constraints : nearly all drug classes Precautionary Notes : Precautionary Notes : potential muscular or neural damage 2.3.Intravenous Route 2.3.Intravenous Route Two types: Two types: IV injection and IV infusion needle or needle or cannulation cannulation Type I_IV injection( vein puncture) Type I_IV injection( vein puncture) Site : large proximal veins Volume : 1~100ml 1~100ml Characteristic Characteristic : extremely rapid and predictable response extremely rapid and predictable response Formulation Constraints Formulation Constraints : solutions and some emulsions Precautionary Notes : Precautionary Notes : Drug shock: too rapid abs. control the injection rate Drug shock: too rapid abs. control the injection rate Thrombosis 3
2.3.Intravenous Route(continued) 2.4.Other Routes Type ll_IV infusion(venoclysis) Intra-arterial route: ◆Site:vein To administer radiopaque contrast agent,to perfuse ·Volume:100-1000ml antineoplastic agent targetly; ·Characteristic LVP:to provide energy,water and dilution effect *Drug:provide continuous and prolonged effect Intrathecal route: Formulation Constraints: Must be especially carefully formulated; solutions and some emulsions: normally need to be isotonic Precautionary Notes: Intradermal route: IV admixtures:must avoid incompatibility;sterility Allergy test,isotonic Qualities of Parenteral Products 3.Compounds and Formulation Manageability of Dosing Volume The availability of the active drug in a parenteral product Comfort: is affected by: Isotonicity,Pyrogen free,pH Physicochemical properties of the drug: drug itself) Stability: chemical,physical,microbial resistance The added substances: ÷Convenience: modifications and assurance in stability,efficiency the least convenient of dosage forms.device improvement and convenience Release of Drug for Absorption: The vehicle(the delivery media) solution disperse systems; Devices give considerable control of release of drug 4
4 2.3.Intravenous Route ( 2.3.Intravenous Route (continued) Type II_IV infusion( Type II_IV infusion( venoclysis) Site : vein Volume : 100~1000ml 100~1000ml Characteristic Characteristic : LVP: to provide energy, water and dilution effect LVP: to provide energy, water and dilution effect *Drug: provide continuous and prolonged effect *Drug: provide continuous and prolonged effect Formulation Constraints Formulation Constraints : solutions and some emulsions: solutions and some emulsions: normally need to be isotonic Precautionary Notes : Precautionary Notes : IV admixtures: must avoid incompatibility; sterility 2.4. Other Routes 2.4. Other Routes Intra-arterial route: arterial route: To administer To administer radiopaque contrast agent, to perfuse contrast agent, to perfuse antineoplastic antineoplastic agent targetly; Intrathecal Intrathecal route: Must be especially carefully formulated; Must be especially carefully formulated; Intradermal Intradermal route: Allergy test, isotonic Qualities of Parenteral Products Manageability of Dosing Volume Comfort: Isotonicity, Pyrogen free, pH Stability: chemical, physical, microbial resistance Convenience: the least convenient of dosage forms, device improvement Release of Drug for Absorption: solution & disperse systems; Devices give considerable control of release of drug 3. Compounds and Formulation 3. Compounds and Formulation The availability of the active drug in a The availability of the active drug in a parenteral parenteral product product is affected by: is affected by: Physicochemical prope Physicochemical properties of the drug; rties of the drug; ( drug itself) ( drug itself) The added substances; The added substances; ( modifications and assurance ( modifications and assurance in stability ,efficiency in stability ,efficiency and convenience ) and convenience ) The vehicle( the delivery media) ( the delivery media) 4
Properties Effect on 3.1.1.Crystal characteristics Molecular structure and weight drug activity Melting point preparation method Of special importance for suspension powders Thermal profile thermal stability,prep method Particle size and shape solubility&stability ÷Including: Hygroscopicity potential hydration,prep.process design and storage lonization constant pH solubility stability Crystal form,habit,density size distribution Light stability stability evaluation method Great effect on the solubility and stability Optical activity Example:IM suspension pH solubility profile stability efficiency pH stability profile ÷Control: Polymorphism potential crystallization,solubility,stability Strictly crystallization control Solvate formation solubility,stability and activity pH,rate of addition,solvent conc.&purity,tem.,mixing rate 3.1.2.Chemical Modification 3.1.3.Polymorphism Parent drug modify new structure,new properties Definition: ÷Prodrug A given chemical has several crystal forms In vivo,modified drug converted into parent drug exhibiting different properties Commonly used:salts of organic compounds Dramatically increase solubility Significantly affect: Weak acids:sodium/potassium salts: Weak bases:hydrochloride/sulfate salts; Solubility,dissolution rate stability Water-insoluble salts: To enhance stability or to prepare a suspension Examples: 5
5 Properties Effect on Molecular structure and weight Molecular structure and weight drug activity Melting point Melting point preparation method Thermal profile t Thermal profile thermal stability, prep method hermal stability, prep method Particle size and shape Particle size and shape solubility& stability solubility& stability Hygroscopicity potential hydration, prep. process design and storage Ionization constant Ionization constant pH solubility & stability Light stability Light stability stability evaluation method Optical activity Optical activity pH solubility profile pH solubility profile stability & efficiency pH stability profile pH stability profile Polymorphism potential crystallization, solubility, stability tion, solubility, stability Solvate formation solubility, stability and activity lubility, stability and activity 3.1.1.Crystal characteristics 3.1.1.Crystal characteristics Of special importance fo Of special importance for suspension & powders r suspension & powders Including: Including: Crystal form, habit, density & size distribution Crystal form, habit, density & size distribution Great effect on the solubility and stability Great effect on the solubility and stability Example: IM suspension Control: Control: Strictly crystallization control Strictly crystallization control pH, rate of addition, solvent conc.& purity, tem., mix pH, rate of addition, solvent conc.& purity, tem., mixing rate 3.1.2. Chemical Modification 3.1.2. Chemical Modification Parent drug modify Parent drug modify new structure, new properties Prodrug: In vivo, modified drug converted into parent drug In vivo, modified drug converted into parent drug Commonly used: salts of organic compounds Dramatically increase solubility Weak acids: Weak acids: sodium/potassium salts; sodium/potassium salts; Weak bases: Weak bases: hydrochloride/sulfate salts; hydrochloride/sulfate salts; Water-insoluble salts: insoluble salts: To enhance stability or to prepare a suspension 3.1.3.Polymorphism Definition: Definition: A given chemical has several crystal forms A given chemical has several crystal forms exhibiting different properties Significantly affect: Significantly affect: Solubility, dissolution rate & stability Examples: Examples: 5
3.1.4.pH and pKa 3.2.Added Substances ÷Purpose: Properties relating to To enhance and ensure the safety,efficiency&stability pH solubility/stability of the drug ÷Requirement:. Important for solution&suspension; Should have a clear purpose and function Should be approved/accepted(type dose) Compatibility of drugs with infusion fluids Classification: Antioxidants,antimicrobial agents,etc. 3.2.1.Antioxidants 3.2.2.Antimicrobial Agents Multi-dose parenteral products: ÷Most commonly used: preservatives required: Salts of sulfer dioxide:bisulfite,metasulfite sulfite Single-dose parenteral products: try to avoid using it ÷Concentration: The reactivity of the drug,the container(type,headspace),dosing Precautionary Notes: (single/multi-).inert gas,expiration date designed Interactions with other components:protein,micelle, oil phase,polymeric package material.Thus...... Alternatives: Must do preservative efficacy test; Deoxygenation of the makeup water.N2 atmosphere,inert gas Careful and thorough preformulation consideration 6
6 3.1.4. pH and 3.1.4. pH and pKa Properties relating to : Properties relating to : pH solubility/stability of the drug Important for solution& suspension; Important for solution& suspension; Compatibility of drugs with infusion fluids 3.2. Added Substances 3.2. Added Substances Purpose: To enhance and ensure the safety, efficiency& stability To enhance and ensure the safety, efficiency& stability Requirement: Requirement: Should have a clear purpose and function Should have a clear purpose and function Should be approved/accepted (type & dose) Should be approved/accepted (type & dose) Classification: Classification: Antioxidants, antimicrobial agents, etc. Antioxidants, antimicrobial agents, etc. 3.2.1. Antioxidants 3.2.1. Antioxidants Most commonly used: Most commonly used: Salts of Salts of sulfer dioxide: dioxide: bisulfite, metasulfite & sulfite Concentration: Concentration: The reactivity of the drug, the container (type, headspace), dos The reactivity of the drug, the container (type, headspace), dosing (single/multi (single/multi-), inert gas, expiration date designed Alternatives: Alternatives: Deoxygenation of the makeup water, N2 atmosphere, inert gas 3.2.2. Antimicrobial Agents 3.2.2. Antimicrobial Agents Multi-dose parenteral parenteral products: preservatives required; preservatives required; Single-dose parenteral parenteral products: try to avoid using it try to avoid using it Precautionary Notes: Interactions with other components: protein, micelle, Interactions with other components: protein, micelle, oil phase, polymeric package material. Thus…… Must do preservative efficacy test; Must do preservative efficacy test; Careful and thorough Careful and thorough preformulation consideration 6
3.2.3.Buffers 3.2.4.Tonicity Adjustment Agents ◆Purpose: ◆Purpose:. To maintain a suitable pH range,thus to assure the To adjust to be isotonic to the blood's osmotic pressure stability. ÷Significance: ÷Requirement:. IV large volume(>100ml),nonisotonic products: Must have sufficient buffer capacity Hypotonic hemolysis(RBC broken) (affected by drug degradation,the container,gas,etc.) Hypertonic crenation ◆Commonly used ÷Commonly used: Acetates,citrates,phosphates,amino acids Dextrose,NaCl,KCI 3.2.5.Protectants One Miliosmolarity (mOsm/kg): the osmolarity produced by ÷Purpose: One mmole non-eletrolyte or One mmole iron Protect the protein and liposomal formulations from stress or adsorption. Blood osmolarity:298mOsm ÷Commonly used: Cryoprotectants and lyoprotectants:case-by-case; 142mmol/L NaCl:142*2=284mOsm Suger and polyhydroxy compounds: HSA:higher level to protect against adsorptive loss. 7
7 3.2.3.Buffers 3.2.3.Buffers Purpose: Purpose: To maintain a suitable pH range, thus to assure the To maintain a suitable pH range, thus to assure the stability. stability. Requirement: Requirement: Must have sufficient buffer capacity Must have sufficient buffer capacity (affected by drug degradation, the container, gas, etc.) (affected by drug degradation, the container, gas, etc.) Commonly used: Acetates, citrates, phosphates, amino acids Acetates, citrates, phosphates, amino acids 3.2.4. Tonicity Adjustment Agents 3.2.4. Tonicity Adjustment Agents Purpose: Purpose: To adjust to be isotonic to the blood To adjust to be isotonic to the blood’s osmotic pressure s osmotic pressure Significance: Significance: IV large volume(>100ml), IV large volume(>100ml), nonisotonic products: products: Hypotonic Hypotonic hemolysis (RBC broken) (RBC broken) Hypertonic Hypertonic crenation Commonly used Commonly used: Dextrose, Dextrose, NaCl, KCl One Miliosmolarity ( mOsm/kg): the osmolarity produced by One mmole non-eletrolyte or One mmole iron Blood osmolarity: 298mOsm 142mmol/L 142mmol/L NaCl: 142*2=284mOsm 3.2.5. Protectants Protectants Purpose: Protect the protein and Protect the protein and liposomal liposomal formulations from stress or formulations from stress or adsorption. adsorption. Commonly used: Commonly used: Cryoprotectants Cryoprotectants and lyoprotectants : case-by-case; Suger and polyhydroxy compounds compounds : HSA: higher level to protect against adsorptive loss. : higher level to protect against adsorptive loss. 7
3.2.6.Other Agents 3.3.Vehicles Aqueous vehicle: ÷Chelating agents: WF/:water for injection,most widely used. EDTA derivatives salts;Citric and tartaric acids; Purification Methods: Inert gases: To eliminate:microorganisms,*pyrogen Filtration,reverse-osmosis,deionization,heating.recirculation Nitrogen,argon,*butyl-rubber stopper; Sterile and bacteriostatic water for injection: Solubilizing agents and surfactants: Must be sterile; Must carefully consider their potential interaction In small volume container; with other components,type,dose,safety 3.3.Vehicles(continued) Purified Water,U.S.P. Water rendered suitable for pharmaceutical purposes by processes such as distillation,ion- exchange treatment (deionization or demineralization),or reverse osmosis.It meets rigid Nonaqueous and Mixed Vehicles specifications for chemical purity,the requirements of the Federal Environmental Protection Agency (EPA)with respect to drinking water,and it contains no added substances.Cannot be used as raw material for parenterals.Common uses are:a rinse for equipment,vials,and ÷Purpose: ampoules,and as make up for cosmetics,bulk chemicals,and oral products.For FDA acceptance,purified water must contain less than 0.5 mg/l of TOC (Total Organic ÷Requirement: Carbon),and less than 100 CFU/ml(Colony Forming Units). Nontoxic,less irritating,inactive,compatible stable; Water For Injection,WFI,U.S.P. is water purified by distillation or by reverse osmosis,it contains no added substance,and it ÷Commonly used: meets the purity requirements under Purified Water.Although not intended to be sterile,it fixed oil:such as corn oil,peanut oil,sesame oil; meets a test for a limit of bacterial endotoxin (less than 0.25 USP Endotoxin Units/ml).It must be produced,stored,and distributed under Sterile Water for Injection. vegetable oil:for steroids. Never used in IV,stricted to IM use. Sterile Water For Injection,U.S.P. A form in which water is distributed in sterile packages.Sterile Water for Injection is intended mainly for use as a solvent for parenteral products such as sterile solids that Water-miscible solvent:glycerin,PEG300,etc. must be distributed dry because of limited stability of their solutions.It must be packaged only in single-dose containers of not larger than 1-liter size 0
8 3.2.6. Other Agents 3.2.6. Other Agents Chelating agents: Chelating agents: EDTA derivatives & salts; Citric and tartaric acids; EDTA derivatives & salts; Citric and tartaric acids; Inert gases: Inert gases: Nitrogen, argon, *butyl Nitrogen, argon, *butyl-rubber stopper; rubber stopper; Solubilizing agents and surfactants: agents and surfactants: Must carefully consider their potential interaction Must carefully consider their potential interaction with other components, type, dose, safety 3.3.Vehicles 3.3.Vehicles Aqueous vehicle: Aqueous vehicle: WFI: water for injection, most widely used. : water for injection, most widely used. Purification Methods: Purification Methods: To eliminate: microorganisms, * To eliminate: microorganisms, *pyrogen Filtration, reverse-osmosis, deionization, heating, recirculation osmosis, deionization, heating, recirculation Sterile and Sterile and bacteriostatic water for injection: Must be sterile; Must be sterile; In small volume container; In small volume container; 3.3.Vehicles( 3.3.Vehicles(continued continued) Nonaqueous and Mixed Vehicles Purpose Purpose : Requirement Requirement : Nontoxic, less irritating, inactive, compatible & stable; Commonly used Commonly used : fixed oil:such as corn oil, peanut oil, sesame oil; as corn oil, peanut oil, sesame oil; vegetable oil: for steroids. vegetable oil: for steroids. Never used in IV, Never used in IV, stricted to IM use. to IM use. Water-miscible solvent miscible solvent : glycerin, PEG300, etc. : glycerin, PEG300, etc. Purified Water, U.S.P. Water rendered suitable for pharmaceutical purposes by processes such as distillation, ionexchange treatment (deionization or demineralization), or reverse osmosis. It meets rigid specifications for chemical purity, the requirements of the Federal Environmental Protection Agency (EPA) with respect to drinking water, and it contains no added substances. Cannot be used as raw material for parenterals. Common uses are: a rinse for equipment, vials, and ampoules, and as make up for cosmetics, bulk chemicals, and oral products. For FDA acceptance, purified water must contain less than 0.5 mg/l of TOC (Total Organic Carbon), and less than 100 CFU/ml (Colony Forming Units). Water For Injection, WFI, U.S.P. is water purified by distillation or by reverse osmosis, it contains no added substance, and it meets the purity requirements under Purified Water. Although not intended to be sterile, it meets a test for a limit of bacterial endotoxin (less than 0.25 USP Endotoxin Units/ml). It must be produced, stored, and distributed under Sterile Water for Injection. Sterile Water For Injection, U.S.P. A form in which water is distributed in sterile packages. Sterile Water for Injection is intended mainly for use as a solvent for parenteral products such as sterile solids that must be distributed dry because of limited stability of their solutions. It must be packaged only in single-dose containers of not larger than 1-liter size 8
4.Dosage Forms and Preparation 4.1.Solutions 4.1.Solutions (continued) Common Procedure: ÷Filling: Dissolve drug and preservatives->adjust the pH,tonicity etc.- →*filtering→*filling→*sterilization 1.Fill volume should be greater than the exact labeled dose; Filtering: (viscosity,retention of the container and the stopper) 1.To remove particulate matter,haze,color etc; 2.Prefiltration:in large-scale production to prevent clogging; 2.Reference table for excess volumes; 3.heat-sensitive drugs,sterile filtration; 4.Adsorption loss:select suitable filter material 4.2.Suspensions 4.2.Suspensions(continued) Very difficult to formulate and produce because of requiring: ÷Components: Active ingredients,aqueous vehicle,surfactant for 1.Excellent stability: wetting,dispersing or suspending agents,preservatives, (ships without caking/settling); buffers sometimes. 2.Critical rheological properties: *syringeability and*injectability Two basic methods: Syringeability: Sterile vehicle powder aseptic combination; Flow properties:container-syringe,dose accuracy; Sterile solutions are combined first and in situ Injectability: crystallization: Flow properites:syringe-vein,evenness of flow; 9
9 4.Dosage Forms and Preparation 4.Dosage Forms and Preparation 4.1. Solutions 4.1. Solutions Common Procedure: Dissolve drug and preservatives adjust the pH, tonicity adjust the pH, tonicity etc. *filtering *filling *steril etc. *filtering *filling *sterilization Filtering: Filtering: 1. To remove particulate 1. To remove particulate matter, haze, color etc; 2. Prefiltration: in large-scale production to prevent clogging; 3. heat-sensitive drugs, sterile filtration; 4. Adsorption loss: select suitable filter material 4. Adsorption loss: select suitable filter material 4.1. Solutions ( 4.1. Solutions (continued continued) Filling: Filling: 1. Fill volume should be Fill volume should be greater greater than the exact labeled than the exact labeled dose; (viscosity, retention of the container and the stopper) 2. Reference table for excess volumes; 2. Reference table for excess volumes; 4.2. Suspensions 4.2. Suspensions Very difficult to formulate and produce because of Very difficult to formulate and produce because of requiring: requiring: 1. Excellent stability: 1. Excellent stability: (ships without caking/settling); 2. Critical 2. Critical rheological rheological properties: properties: *syringeability and * injectability Syringeability: Flow properties: container syringe, dose accuracy; Flow properties: container syringe, dose accuracy; Injectability: Flow properites: syringe vein, evenness of flow; : syringe vein, evenness of flow; 4.2. Suspensions ( 4.2. Suspensions (continued continued) Components: Components: Active ingredients, aqueous vehicle, surfactant for Active ingredients, aqueous vehicle, surfactant for wetting, dispersing or suspending agents, preservatives, wetting, dispersing or suspending agents, preservatives, buffers sometimes. buffers sometimes. Two basic methods: Two basic methods: Sterile vehicle & powder aseptic combination; Sterile vehicle & powder aseptic combination; Sterile solutions are combined first and in situ Sterile solutions are combined first and in situ crystallization; 9
4.3.Emulsions 4.4.Dry Powders Rarely used as parenteral products because of: Excellent stability requirement; Particle size<1um,homodispersity; ÷Purpose: Very limited selection of stabilizers emulsifiers; To overcome the intrinsic instability of the drug.be reconstituted before use. ÷Commonly used: w/o,allergy test,SB Production Method: o/w,sustained-release,depot,IM o/w,nutrient emulsion,IV 1.Freeze-drying; 2.Aseptic crystallization and dry powder filling: ÷Fat emulsions:. 3.Spray-drying o/w type,use triglycerides as central core,phospholipid as emulsifier,to provide essential fatty acids and calories. 4.4.1.Freeze-drying (/yophilize) Lyophilisation-Freeze drying ÷Advantages: Sublimation of water from freezed sample Avoid damage to heat-sensitive drugs High specific surface are facilitating complete rehydration Water Improvement in filling accuracy Practical problems Ensure a quick and secure freezing prior 0.0075°C to drying 610 N/m Disadvantages: Sublimation occurs only from the Ice surface- Protective agents needed large surface area/volume Water Stability changing,crystalline/amorphous Removal of the vapour vapour High-cost and complicated The product can most of the time NOT be sterilized container- Temperature sterilizable equipment From www.food.Ith.se/2005/Lectures202005, "Manufacturing of sterile products" 10
10 4.3. Emulsions 4.3. Emulsions Rarely used as Rarely used as parenteral parenteral products because of products because of : Excellent stability requirement; Excellent stability requirement; Particle size<1um, homodispersity; Particle size<1um, homodispersity; Very limited selection of stabilizers & emulsifiers; Very limited selection of stabilizers & emulsifiers; Commonly used: Commonly used: w/o, allergy test, SB o/w, sustained-release, depot, IM o/w, nutrient emulsion, IV Fat emulsions: Fat emulsions: o/w type, use triglycerides as central core, type, use triglycerides as central core, phospholipid as emulsifier, to provide essential fatty acids and calories. 4.4.Dry Powders 4.4.Dry Powders Purpose: Purpose: To overcome the intrinsic instability of the drug, be To overcome the intrinsic instability of the drug, be reconstituted before use. reconstituted before use. Production Method: Production Method: 1. Freeze-drying; drying; 2. Aseptic crystallization and dry powder filling; n and dry powder filling; 3. Spray-drying 4.4.1. Freeze 4.4.1. Freeze-drying ( drying (lyophilize lyophilize) Advantages: Avoid damage to heat Avoid damage to heat-sensitive drugs High specific surface are facilitating complete High specific surface are facilitating complete rehydration Improvement in filling accuracy Disadvantages: Disadvantages: Protective agents needed Stability changing, crystalline/amorphous Stability changing, crystalline/amorphous High-cost and complicated Lyophilisation Lyophilisation-Freeze drying Freeze drying Sublimation of water from freezed Sublimation of water from freezed sample Practical problems Practical problems Ensure a quick and secure freezing prior Ensure a quick and secure freezing prior to drying Sublimation occurs only from the Sublimation occurs only from the surfacelarge surface area/volume Removal of the vapour The product can most of the time NOT be sterili be sterilized containersterilizable equipment Ice Water Water vapour Temperature 0.0075°C 610 N/m2 From www.food.lth.se/2005/Lectures202005, “Manufacturing of sterile products” 10