pharmaceutical solutions pharmaceutics (phm224y/phc330y) gregory poon, phd, bscphm, rph
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Solution: definition
• Homogeneous mixture of two or more substances• May exist in any phase
• Vinegar is acetic acid (and other stuff) in H2O
• Air is a solution of N2, O2, CO2, etc.
• Steel is a solution of iron and carbon
• We will focus liquid solutions, with H2O or oil as solvent
• Solute must be “dissolved” in solvent• Not suspensions
Concentration units
• Molarity (M)• mol/L solution• Temperature dependent due to dV/dT (expansivity)
• Molality (m)• mol/kg solvent• Not temperature dependent
• Mole fraction (X)
• Not commonly used pharmaceutically
1
ii k
jj
n
n
Of k components
More concentration units
• Assume 1 g = 1 mL i.e., = 1• Weight percent
• g/100 mL = 10 mg/mL solution (w/v)• g/100 g = 10 mg/g (w/w)
• Cream, ointment, gel, etc.• Volume percent
• mL/100 mL solution (v/v)• Parts per thousand/million/billion (ppt, ppm, ppb)
• ppt = 1 g/1000 mL = 1 g/L• ppm = 1 mg/L• ppb = 1 µg/L• Commonly used to express contamination
Other concentration definitions
• H2O2
• Commercial H2O2 expressed as x-volume strengths• 1 vol solution produces 10 vol O2 (at STP) when
completely decomposed
• 3% w/v solution = 10 vol• Activity units
• Vitamin A, D• Enzymes, bioactive proteins
• Heparin• Based on arbitrary definition of activity under specified
conditions (temperature, pH, etc.)• No correspondence to amount due to (im)purity
2 2 2 2H O ½O + H O
Pharmaceutical solutions: consideration
• Route of administration• Oral, IV, IM, SC, nasal, rectal, etc.
• Stability of drug solute• Physicochemical• Contamination
• Purity• Microbial• Chemical
• Containers• Organoleptic factors (oral)
Pharmaceutical solutions: advantages
• Easy to dose from concentrate by simple dilution• Easy to mix if necessary• Easy to measure accurately
• Volumetric devices can be very precise and accurate if YOU take care
• Easy to administer orally to children and disabled persons• Amenable to administration by any route
• Ex: suspension cannot be given IV• No lag time due to dissolution
• Rapid onset of action
Pharmaceutical solutions: disadvantages
• Solution chemistry poses many stability issues• Physicochemical degradation
• Shelf life, storage requirement• Reactivity
• Containers, tubing, etc.• Shorter expiry than other dosage forms
• Additional sterility concerns• Solubility may be limiting• Need to mask taste (oral)
• Ex: suspension is “harder” to taste
Solutions: many appellations
• Aromatic waters• + volatile oil
• Aqueous acids• Diluted acids
• Douches• Enemas
• Rectal or oral• Gargles• Mouthwashes• Irrigation solutions• Syrups
• Concentrated sugar solution• Elixir
• Used to contain EtOH• Liniments
• + organics, oil• Spirits
• Peppermint water, rosewater
• Acetic acid, HCl(aq)
• Phosphate enema
• NS for irrigation• Simple syrup (75% sucrose)
• Aromatic ammonia spirit
Composition of pharmaceutical solutions
• Drug• Solvent
• Water, possibly with “premade” matrix• D5W, NS, Ringer’s, NaHCO3, etc.
• Oil• Cosolvent if needed for solubility• Cosolute
• Buffer (for pH)• Additional salts and/or nonelectrolytes
• Adjust tonicity• Preservatives
• Against microbial contamination• Against chemical degradation
• Colour, flavouring agents (oral only)
Pharmaceutical solutions: solvent
• “Purified water” (PW) according to USP 23• Potable water must be further purified for pharmaceuticals
• Remove organic and ionic contaminants• Total organic carbon (<500 ppb)
• Resistivity (e=RA/l [R m]; >17 M•m at pH 7.0)
• Methods• Reverse osmosis (cellulose acetate filters)
• Often feed water for further purification• Double distillation (>10 M•m)• Ion exchange resin (>18 M•m)
• Product is generally also “sterile”, though not relied on as such (<100 cfu/mL)
Pharmaceutical solutions: oil
• Usually IM, sometimes po• Of vegetative origin
• Less saturated, lower melting temperature• Keep the vegetarians happy• Ex: peanut, sesame, corn, cottonseed
• Becomes rancid when oxidized• Must not contain substances that cannot be metabolized
• Mineral oil, paraffin, etc.• Esters of fatty acids give less viscous liquid and easier to
inject
+ -
+-
-
[H ][A ]
[HA]
[HA][H ]
[A ]
[A ]pH p log
[HA]
a
a
a
K
K
K
HA H+
A
CH3COOH CH3COO-H+
C NH3+
CH2OH
CH2OH
CH2OH
C NH2
CH2OH
CH2OH
CH2OH
H+
+
+
+
pKa at 25°C
4.75
8.1
Tris base
+ - -3[HA] [H O ], [A ] [OH ]
Henderson-Hasselbalch
pKa at 25°C
Acetic acid CH3COOH 4.75
Citric acid 3.13 4.76 6.40
Cacodylic acid CH3AsOOH 6.27
Carbonic acid H2CO3 6.37 10.32
Phosphoric acid H3PO4 2.12 7.21
2-morpholinoethanesulfonate (MES) 6.15
Tris 8.1
Boric acid H3BO4 9.14 12.74 13.8
Glycine H3N+•CH2•COOH 2.35 9.78
O N+
CH2CH2SO3-
H
C NH3+
CH2OH
CH2OH
CH2OH
CH
COOH
HOOC
COOH
Some biologically and pharmaceutically important buffers
-[A ]pH p log
[HA]aK
H+
OH-
HA H+
A
H2O
+
+Kw
Ka
+ 3 + 2 +[H ] ( )[H ] ( )[H ] 0b a w a a a wc K K c K K K
Buffer capacity and autoionization of water
Infinite dilution of any acid or base will lead to pH neutrality!
1E-8 1E-7 1E-6 1E-5 1E-4 1E-3 0.01 0.1
4.5
5.0
5.5
6.0
6.5
7.0
Ionization ofbuffer dominates
Autoionizationof water dominates
pH
[total acetate]/M
Equimolar acetate buffer
All roads lead to Rome … sort of
To make a 50 mM potassium acetate solution …
• Dilute 50 mmol acetic acid in ~950 mL water, add concentrated KOH to pH 4.5, and qs to 1 L.
• Dissolve 50 mmol potassium acetate in ~950 mL water, titrate pH to 4.5 with concentrated HCl, and qs to 1 L.
• Dissolve 50 mmol potassium acetate in ~950 mL water, titrate pH to 4.5 with glacial acetic acid, and qs to 1 L.
• Mix 25 mmol acetic acid and 25 mmol potassium acetate to make 1 L of solution.
H+
AHA +Ka
1
2 2 1
ln
(1/ )
1 1ln
a ion
a ion
a
d K H
d T R
K H
K R T T
Thermodynamics of acid-base equilibria: temperature effects
Kozlov and Lohman (2000)
Poon et al. (2002)
van’t Hoff equation
0p
HC
T
Hion
Thermodynamics of acid-base equilibria: salt effects
H+
AHA +Ka
Conditions that stabilize HA decrease Ka
Conditions that stabilize A-
increase Ka
Conjugate pairs differ by (at least) their net charges, so electrostatic interactions are likely important factors for their relative stabilities.
A-
Na+
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O Na+
Na+
Na+Na+Na+Na+
Na+
H2O
H2O
H2OH2O
H2O
Na+
H2OH2OH2O H2O
Ions with multiple and/or unshielded charges (high charge density) are highly susceptible to electrostatic interactions
Ex: phosphates, borates
But not Tris, MES, etc. (Why?)
25 mM NaHPO4
[NaCl]/M pH
0 8.2
0.1 7.8
0.2 7.4
0.5 7.0
1.0 6.4
Poon and Macgregor, unpublished
O N+
CH2CH2SO3-
H
C NH3+
CH2OH
CH2OH
CH2OH
Beispiel
2
B
el
DkT
Dielectric constant
Bjerrum length:Charge separation at which coulomb energy equals the thermal energy kT
Thermodynamics of acid-base equilibria: solvent effects
This other dude is his buddy J. N.
Brønsted
At 25°C…
…in vacuo or in air (D 1), lB = 56.0 nm
…in H2O (D = 79), lB 0.714 nm
So ionic bonds are much weaker in H2O; unpaired charges in nonpolar environment are highly unfavoured
2
B
el
DkT
Choosing a buffer salt
• What pH?• pKa = pH ± (0.5 to 1)• At what temperature?! At what ionic strength?!• (At what pressure?)
• Compatibility with other solutes• Neutral salts• Common ion effect
• Phosphates with Ca2+, Mg2+, Zn2+, Mn2+, Cu2+…• Tris with Ag+
• Metal chelation• Tris, tricine, EDTA, EGTA, etc.
• Toxicity• Cacodylate, oxalate, etc.
Specific issues
• Carbonate
• Prone to buffer loss due to dehydration to CO2
• Carbonate buffer <pH 7 will burst into
• Buffers with multiple closely-spaced pKa
• Citrate, succinate, etc.• Susceptible to pH hopping• Lowest and highest pKa useable as one-way buffer• Not many friendly buffers for pH 5 to 6
• Careful with buffer salts of marginal solubilities• Na vs. K
• Titrate pH AFTER you are done with all the solutes, not BEFORE!
Pharmaceutical solutions: cosolvent
• Organic liquid used to increase solubility of lipophilic drugs• EtOH, glycerol, PG, PEG, cyclodextrin
• For acid or base, increases solubility of unionized drug (S0)
• Alters activity of water• Changes pKa• May precipitate ionic cosolutes
app 0 ionized
pH p0 0
pH p0
10
(1 10 )
a
a
K
K
S S S
S S
S
Chemical stability of solutions
• Main chemical pathways are hydrolysis, oxidation and photochemistry
• Hydrolysis• Ex: ASA
• Difficult to avoid in aqueous solution• Different mechanisms depending on pH
• Keep pH near neutral if feasible• First order in aqueous solution
• Zero order in suspension
COOHO
CH3
OH2
COOH
OHCH3COOH+
Oxidation in solution
• Dissolved O2 from air
• Catalyzed by trace transition metals• Cu, Ni, Fe, Mn, Co, etc.• Contaminants from drug and solutes from which
solution was made• Ex: captopril (Lee and Notari, 1987)
• Oxidation of oily vehicle (rancid)• Strategies
• Purge with inert gas, usually N2
• Antioxidants, EDTA (chelates free metal ions)
NSH
CH3
O
HOOC
N NS
CH3
O
HOOC
S
CH3
O
COOH
O2
Cu2+
Some antioxidants
• Electron-rich molecules and happy to share!
Butylated hydroxy anisole (BHA) Butylated hydroxy toluene (BHT)
Tocopherols Ascorbate
Propyl gallate
Photochemical degradation
• Absorption of incident photon• Usually UV, but visible photon may be energetic enough
• Often results in oxidation of susceptible group• Ex: nifedipine
• Mechanistically linked to phototoxicity of some drugs• Keep in light-tight containers
Antimicrobial preservatives
• Enemies• Bacteria• Yeast and mold
• Alcohol• Ethanol (>10%)• Propylene glycol (15-30%)
• Organic acids• Only unionized fraction active (why?)• Examples:
• Benzoic acid <0.1% (pKa 4.5)• Sorbic acid <0.1% (pKa 4.8)• Acetic acid (pKa 4.7)
• Limited by taste
More antimicrobials
• Parabens <0.1% (pKa 8.5) (esters)• Solubility decrease with increasing R• Ester can also hydrolyze
• Quaternary ammonium salts <0.02%
• Highly water soluble• Acts as surfactant• Not active against Gram-negative bacteria (why?)
• Nitrite (cured meat)• Active against C. botulinium• Carcinogenic
• Sulfites (wine)• Allergen, flavour problems
Antimicrobials: summary
• Defined effective pH ranges
• Some also double as antioxidants• Sorbate, sulfites
• Oily solutions: surfactants, ex: hexylresorcinol
Agent pH Range
Benzoic acid 2.5-4.0 Sorbic acid 3.0-6.5Proprionic acid 2.5-5.0Acetic acid 3.0-5.0Parabens 3.0-9.0Sulfites 2.5-5.0Nitrites 4.0-5.5
Endotoxins
• Lipopolysaccharide (LPS) complex associated with outer cell membrane of Gram-negative bacteria
• Strongly pyrogenic, canlead to septic shock
• Very persistent• Harsh removal
• 250°C x 45 min.• Strong alkali or
oxidizer• Limit for WFI: 0.25 U/mL• Only good strategy is test
vigorously and avoidsources
Pharmaceutical solutions: tonicity
• Important especially for parenteral solutions• Paratonic solutions can present significant osmotic toxicity
• Hypotonic (cells explode)• Hypertonic (cells crenate)• Pain!
• Can use hypertonicity as an antimicrobial strategy• Ex: sucrose solution (>60%) is self-preserving
• Remember osmotic pressure () is colligative property• Not specific to any particular solute• Implications for strong and weak electrolyte
• Ex: NaCl vs. NaAc• pH dependence
Tonicity: more subtle than osmotic pressure
• “Iso-osmotic” does NOT imply “isotonic”• Some solutes cannot penetrate certain membranes
• Ex: boric acid and mannitol cannot enter RBC• Iso-osmotic solution will be hypertonic if given IV!
• Must consider specificity of tissue being exposed• Ex: boric acid okay for ophthalmic and nasal tissues
• Paratonic solutions can be intentional• SC injections
• Fatty tissue more tolerant• IM injections
• Hypertonic formulation to draw in water for more rapid absorption
• Ex: IM diazepam
Oral solution: biopharmaceutics
• No dissolution phase• Major concern is physicochemical stability and interaction
with other substances in GI fluid• Change in pH• Dilution of cosolvent• Formation of insoluble complexes
• Ciprofloxacin with Fe2+, Ca2+, Mg2+ etc.• Viscosity of solution may slow absorption
• Assuming spherical drug molecule
• So really, please drink a glass of water
ƒ 6
kT kTD
r
Parenteral solutions
• IV, IM, sc, intra-articular, intrathecal, etc.• Injected directly into body … unique requirements
• Manufacturing (purity/sterility of components)• Preparation and admixture (asceptic technique, laminar
flow hood)• Administration
• “Water for Injection” (WFI) (USP 23)• Prepared by distillation or 2-stage RO• Stored and distribution at 80°C to inhibit growth• Can be stored at room temperature for <24 h• Chemical purity same as PW
• Basis for many vehicles for reconstituting/diluting parenterals• NS, dextrose, Ringer’s dextrose, etc.
Sterility of parenteral solutions
• Single-dose products may be preservative-free• Antimicrobials must be added to multiple-dose products• “Pharmacy bulk package”
• For admixture programs thatprepare many individual doses
• Used in LF hoods• Exempt from antimicrobial if
<30 mL• Specially labelled
Incompatibility in admixtures
• Physical• Generally precipitation due to pH change, common ion
effect, insoluble salt combinations• Ex: Ca and phosphate in TPN, weak organic acids
precipitating at low pH• Chemical
• Covalent interactions• Ex: lactams and aminoglycosides
• Therapeutic• Can be very subtle
• Many incompatibilities are empiricallydetermined• Consult a reference
Containers
• Grave concern for parenteral containers• Potential physical problems
• Leaching• Permeation• Adsorption
• Plastic containers (PVC, PE/PP copolymer)• Vials, IV bags• Permeation most significant problem
• Minimize by overwrapping• Lipophilic molecules can adsorb
• Ex: vitamin A, insulin• Nitroglycerin
Glass: some properties
• Glass is amorphous SiO2
• Doped/contaminated withionic substances duringmanufacture
• Soda (Na2CO3)
• Potash (K2CO3, etc.)
• Lime (CaO), etc.• Interstitial, can migrate
• “Soda-lime glass”
• Ions can hydrolyze ( pH) in H2O, catalyze oxidation, etc.
• Glass can be attacked by solution and release glass flakes
USP classification of glass containers
• Type I: borosilicate glass• Pyrex, Kimax, (Duran)• Addition of boron affords chemical (durability)
and heat resistance (small dV/dT)• Suitable for all products
• Type II: treated soda-lime glass• Treated with Freon or SO2 dealkalize• Greater durability• Suitable if buffered at pH <7
• Type III: soda-lime glass• For non-aqueous liquids or dry powder
• Type IV: Non-parenteral (NP)• Durability determined by release of alkali released into
distilled H2O under specific conditions of heat and pressure
USP: more on containers
• Single-dose containers• Volume limited to <1000 mL
• Multi-dose containers• Volume <30 mL (pharmacy bulk package)• Rubber septum to minimize contamination
• Must also be physically compatible with solution• Same applies to connections, lines, ports, etc.• Leaching can be reduced by coating with Teflon, etc.
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