PARENTERAL DRUG FORMULATIONS ________________________________________________________________

PARENTERALS para: outside enteron: intestine (i.e. beside the intestine) These are the preparations which are given other than oral routes. Injections: These are Sterile, Pyrogen free preparations intended to be administered parenterally (outside alimentary tract).

Necessities of Parenteral preparations: Sterility (must) Pyrogen (must) Free from particulate matter (must) Clarity (must) Stability (must) Isotonicity (should) Solvents or vehicles used must meet special purity and other standards. Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents. Must be prepared under aseptic conditions. Specific and high quality packaging.

General steps involved 1. Cleaning 2. Preparation of bulk products 3. Filtration 4. Filling of solution in or product in ampoule or vial 5. Sealing 6. Sterilization 7. Tests for Quality control

Parental Routes of Administration: Most Common: 1. Subcutaneous (SC; SQ ;Sub Q) 2. Intramuscular (IM) 3. Intravenous (IV) Others: 4. Intra-arterial (IA) 5. Intrathecal 6. Intraarticular 7. Intrapleural 8. Intracardial 9. Intradermal (Diagnostic)

Routes of Parenteral Administration Subcutaneous (21) Intravenous (21) Intramuscular (20) Intradermal (23) Intra arterial (20-22) Epidermis Dermis Vein Subcutaneous tissue Artery Muscle

Formulation of Parenteral: Therapeutic agents Vehicles Water Water miscible vehicles Non- aqueous vehicles Added substances (Additives) Antimicrobials Antioxidants Buffers Bulking agents Chelating agents Protectants Solubilizing agents Surfactants Tonicity- adjusting agents

Formulation of Parenteral 1. Active Pharmaceutical Ingredients (API): Antibiotics Anticancer Steroids Vaccines Antipyretic Analgesics Anti- inflammatory LVP’s like Dextrose, NaCl or combination etc

API Profile: Solubility in different solvents (parentally acceptable solvents / co-solvents) Partition Coefficient (octanol:water) pH Solubility Forced degradation Study

API Profile The stability of API (forced degradation study) Thermal Stress: A 1 mg/mL sample in a 10:90 acetonitrile:water or any suitable solvent mixture and heated to 100°C for 30 minutes and then to be assayed. Acidic Stress: mixing 0.1 mL of a 10 mg/mL of sample in acetonitrile solution or any suitable solvent with 0.1 mL of either 1 N or 12.1 N HCl and be allowed to react for 24 hours. Basic Stress: Sample solution in acetonitrile or any suitable solvent be treated with buffered saline having pH of 8. Oxidative Stress: mixing an equal volume of drug solution in acetonitrile or any suitable solvent with 30% hydrogen peroxide solution and allowed to react for 24 hours.

Formulation of Parenteral 2. Solvents: Water Should meet compendial requirements Water miscible vehicles Ethyl alcohol PEG PG Non aqueous vehicles Fixed oils

Formulation of Parenteral Solvents Solvents used must be: Non-irritating Non-toxic Non-sensitizing No pharmacological activity of its own Not affect activity of medicinal

Formulation of Parenteral 3. Added substances (Additives) Antimicrobials: Added for fungistatic or bacteriostatic action or Used to prevent the multiplication of micro-organisms; concentration Benzyl alcohol ------ 0.5 – 10 % Benzethonium chloride -- 0.01 % Methyl paraben ---- 0.01 – 0.18 % Propyl paraben --- 0.005 – 0.035 % Phenol --- 0.065 – 0.5 %

Antioxidants: Used to protect product from oxidation Acts as reducing agent or prevents oxidation Ex: A) Reducing agent: Ascorbic acid -- 0.02 – 0.1 % Sodium bisulphite-- 0.1 – 0.15 % Sodium metabisulphite -- 0.1 – 0.15 % Thiourea - 0.005 % B) Blocking agents: Ascorbic acid esters- 0.01 – 0.015% BHT- 0.005 – 0.02 % C) Synergistic: Ascorbic acid , Citric acid , Tartaric acid D) Chelating agent: EDTA- 0.01- 0.075 %

Buffers: Factors affecting selection of buffers: EXAMPLES: Added to maintain pH, Change in pH may causes degradation of the products Acetates, citrates, phosphates are generally used. Factors affecting selection of buffers: Effective range, Concentration Chemical effect on the total product EXAMPLES: Acetic acid ,adipic acid, benzoic acid, citric acid, lactic acid Used in the conc. of 0.1 to 5.0 %

Chelating agents: Examples: Used to form the complex with the metallic ions present in the formulation so that the ions will not interfere during mfg. of formulation. They form a complex which gets dissolved in the solvents. Examples: Disodium edetate - 0.00368 - .05 % Disodium calcium edetate - 0.04 % Tetrasodium edetate - 0.01 %

Stabilizers: Examples: As parenterals are available in solution form they are most prone to unstabilize Used to stabilize the formulation Maintain stable Examples: Creatinine – 0.5- 0.8 % Glycerin – 1.5 – 2.25 % Niacinamide – 1.25 -2.5 % Sodium saccharin – 0.03 % Sodium caprylate – 0.4 %

Solubilizing agents: Examples: Used to increase solubility of slightly soluble drugs they acts by any one of the following: solubilizers, emulsifiers or wetting agents. Examples: Dimethylacetamide, Ethyl alcohol Glycerin Lecithin PEG – 40 castor oil PEG – 300 Polysorbate 20, 40, 80

Tonicity- adjusting agents: Used to reduce the pain of injection. Buffers may acts as tonicity contributor as well as stabilizers for the pH. Isotonicity depends on permeability of a living semipermeable membrane Hypotonic : swelling of cells (enlargement) Hypertonic: shrinking of cells (reduction) Example: Glycerin Lactose Mannitol Dextrose Sodium chloride Sorbitol

Formulated Product Stability Studies Finished product stability is tested according to International Conference on harmonization (ICH) guidelines.