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Parenteral Products

Parenteral Products. administration by injection. i.v., i.m., s.c., i.d. Solution Formulation. solvents must meet purity standards restricted number and kind of added substances no coloring agents permitted products are always sterilized products are pyrogen-free

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Parenteral Products

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  1. Parenteral Products • administration by injection. • i.v., i.m., s.c., i.d. CHEE 440

  2. Solution Formulation • solvents must meet purity standards • restricted number and kind of added substances • no coloring agents permitted • products are always sterilized • products are pyrogen-free • products prepared in environmentally controlled areas under sanitary conditions • volumes used are specific to application CHEE 440

  3. Components • water • water for injection • sterile water for injection • active agent • need to consider solubility • anti-oxidants • ex. ascorbic acid, sodium bisulfite • buffers • e.g. citric acid, sodium phosphate, sodium acetate, dipotassium hydrogen phosphate • chelating agents • inactivate metals which catalyze degradation • co-solvents • e.g. ethanol, PEG, glycerin • tonicity agents • related to semi-permeable nature of cell membranes and osmotic pressure of solution • preservatives CHEE 440

  4. Preservatives • Criteria • effective • soluble • sufficiently non-ionized in solution • nonirritating, nonsensitizing, nontoxic • chemically stable • compatible with other ingredients • Types • antifungals • benzoic acid, parabens, sodium benzoate, sodium propionate • antimicrobials • benzyl alcohol, phenol, chlorobutanol, cetylpryidinium chloride CHEE 440

  5. Osmotic Pressure : Clinical Relevance • whole blood, plasma, serum are complex mixtures of proteins, glucose, non-protein nitrogenous compounds, and electrolytes (Na, Ca, K, Mg, Cl, CO3 ) • electrolytes determine osmotic pressure • must formulate with osmotic pressure in mind • Osmotic activity is a colligative property • depends on number of molecules present • freezing point depression • boiling pt elevation • osmotic pressure CHEE 440

  6. Osmotic Pressure, P • water moves across a semi-permeabl membrane due to DmL to R • at equilibrium mw,R = mw,L nonideal solutions : ideal solutions : ideally dilute solutions : CHEE 440

  7. Boiling Point Elevation • boiling pt of solution is higher than that of pure solvent • consider a vapor in equilibrium with a solution at constant pressure • for very dilute solutions : • Kb = ebullioscopic constant (Tables) • Kb water = 0.51 K kg/mol CHEE 440

  8. Tonicity • extent of swelling or contraction of biological membrane (cells, mucous membranes) • cell membranes are semipermeable • hypertonic = higher P than cells • causes cells to crenate or shrink • hypotonic = lower P than cells • causes cells to rupture (lyse) • isotonic = same P (isoosmotic) CHEE 440

  9. Freezing Point Depression • assume solvent freezes as pure solvent • Kf = cryoscopic constant (Tables) • Kf water = 1.86 K kg/mol CHEE 440

  10. Electrolyte Solutions • Van’t Hoff Factor, i • accounts for nonideality, increased number of moles produced ideally dilute CHEE 440

  11. Methods of Adjusting Tonicity • DTf blood and tears = - 0.52˚C • add appropriate amount of compound (ex. NaCl) to drug solution or add water to drug solution • NaCl Equivalent Method • E = amount of NaCl equivalent in P to 1 g of drug • NaCl (w/v%) = 0.90 - E*[drug] (w/v%) • values for E found in Tables (p 622-7 Remington) CHEE 440

  12. Methods of Adjusting Tonicity • White-Vincent Method (USP Method) • calculates volume (V) in ml of isotonic solution that can be prepared by mixing drug with water/isotonic buffered solution • V = w * E *111.1 • w = wt. of drug (g) CHEE 440

  13. Methods of Adjusting Tonicity • Freezing Point Depression • freezing point depressions of 1w/v% drug solutions (DTf1%) have been tabulated (p 622-627 Remington) • choose appropriate solute for adjusting tonicity • using DTf,ref1% determine required amount (wref) to cover remaining DTf • Vreq = volume of water required • C = drug concentration (w/v%) CHEE 440

  14. Example : • 1. Make a 25 ml isotonic solution of 2.5 w/v % epinephrine bitartrate. • 2. Do the same but now add 0.5w/v % phenol. CHEE 440

  15. Buffers • compounds or mixtures which resist changes in their pH • typically a combination of a weak acid and its conjugate base (salt) or a weak base and its conjugate acid • ex. acetic acid and sodium acetate • to determine pH of buffer solution • weak acid + salt • weak base + salt • valid for 4 < pH < 10

  16. Buffers • buffer capacity, b • the amount of resistance to change in pH • maximum capacity • when pH = pKa

  17. Buffers : clinical significance • drugs • many exert some buffering action • biological buffers • blood • pH ≈ 7.4 (7.0-7.8) • bblood ≈ 0.031 • lacrimal fluid • pH ≈ 7.4 (7-8) • large b (15 x dilution) • reaction with tissue • want pH formulation ≈ pH body fluid • don’t want a strong capacity

  18. Buffers • preparation • select weak acid with a pKa near desired pH • use buffer capacity eqn to calculate [acid]:[salt] ratio • a suitable buffer has a [salt] + [acid] = 0.05 - 0.5 M and a capacity of 0.01 - 0.1 • check tonicity

  19. Containers CHEE 440

  20. Freeze Drying • used to dry heat-sensitive materials liquid P solid vapor T CHEE 440

  21. Freeze-Drying • advantages • degradation of product is minimized • light, porous product • no concentration of product during drying • disadvantages • product is very hygroscopic • slow and expensive process CHEE 440

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