Parenteral Products

1
Parenteral Products

• administration by injection.
• i.v., i.m., s.c., i.d.

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

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

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

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

6
Osmotic Pressure, P
at t 0
sucrose solution
water
semipermeable membrane
at equilibrium
h
7
Osmotic Pressure, P

• water moves across membrane due to DmL to R
• at equilibrium mw,R mw,L

nonideal solutions
ideal solutions
ideally dilute solutions
8
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

9
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)

10
Freezing Point Depression

• assume solvent freezes as pure solvent
• Kf cryoscopic constant (Tables)
• Kf water 1.86 K kg/mol

11
Electrolyte Solutions

• Vant Hoff Factor, i
• accounts for nonideality, increased number of
  moles produced

ideally dilute
12
Methods of Adjusting Tonicity

• DTf blood and tears - 0.52C
• 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 - Edrug (w/v)
• values for E found in Tables (p 622-7 Remington)

13
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)

14
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)

15
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.

16
Containers
17
Freeze Drying

• used to dry heat-sensitive materials

liquid
P
solid
vapor
T
18
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