Pharmaceutical solutions

Pharmaceutics (PHM224Y/PHC330Y)

Gregory Poon, PhD, BScPhm, RPh

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

Strong acid/strong base titration

Weak acid/strong base titration

Buffering in action

+ -

+-

-

[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.