B. AmsdenCHEE 440 Parenteral Products administration by injection.  i.v., i.m., s.c., i.d.

B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 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, CO 3 )  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

B. AmsdenCHEE 440 Osmotic Pressure,  water moves across a semi-permeabl membrane due to  L to R at equilibrium  w,R =  w,L nonideal solutions : ideal solutions : ideally dilute solutions :

B. AmsdenCHEE 440 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 : K b = ebullioscopic constant (Tables) K b water = 0.51 K kg/mol

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

B. AmsdenCHEE 440 Freezing Point Depression assume solvent freezes as pure solvent  K f = cryoscopic constant (Tables)  K f water = 1.86 K kg/mol

B. AmsdenCHEE 440 Electrolyte Solutions Van’t Hoff Factor, i  accounts for nonideality, increased number of moles produced ideally dilute

B. AmsdenCHEE 440 Methods of Adjusting Tonicity  T f blood and tears = ˚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  to 1 g of drug NaCl (w/v%) = E*[drug] (w/v%) values for E found in Tables (p Remington)

B. AmsdenCHEE 440 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)

B. AmsdenCHEE 440 Methods of Adjusting Tonicity Freezing Point Depression  freezing point depressions of 1w/v% drug solutions (  T f 1% ) have been tabulated (p Remington)  choose appropriate solute for adjusting tonicity using  T f,ref 1% determine required amount (w ref ) to cover remaining  T f V req = volume of water required C = drug concentration (w/v%)

B. AmsdenCHEE 440 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.

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

Buffers buffer capacity,   the amount of resistance to change in pH  maximum capacity when pH = pK a

Buffers : clinical significance drugs  many exert some buffering action biological buffers  blood pH ≈ 7.4 ( )  blood ≈  lacrimal fluid pH ≈ 7.4 (7-8) large  (15 x dilution) reaction with tissue  want pH formulation ≈ pH body fluid  don’t want a strong capacity

Buffers preparation  select weak acid with a pK a near desired pH  use buffer capacity eqn to calculate [acid]:[salt] ratio  a suitable buffer has a [salt] + [acid] = M and a capacity of  check tonicity

B. AmsdenCHEE 440 Containers

B. AmsdenCHEE 440 Freeze Drying used to dry heat-sensitive materials P T liquid vapor solid

B. AmsdenCHEE 440 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