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