Drugs In Solution Draft Notes PDF

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PHAR1812 - 2013 21Principal phases in drug actionAdministrationDisintegrationDissolutionAbsorptionDistributionEffectEliminationFirst primary method is through a tablet, and then we will look at different forms of administration. A tablet is swallowed. Then the tablet needs to disintegrated into smal...

Description

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Principal phases in drug action

Administration

Disintegration

Dissolution

Absorption

Distribution

Effect

Elimination

First primary method is through a tablet, and then we will look at different forms administration. A tablet is swallowed. Then the tablet needs to disintegrated into small particles (not dissolution, rather smaller insoluble particles). The drug is then designed to dissolve into the gastrointestinal tract (because it can go any further unless it is dissolved). If its not dissolved it will come out straight the other end and won't have any effect. Dissolution is essential or the process sto Once dissolved it is absorbed across the membranes of the gastrointestinal tract, a then into the blood. This is an important process because it is within the blood where it is distributed the body (i.e. if a headache is the problem, it needs to transport across the body an transport process is within the blood). Gets to where it needs to and has its effect. To have its effect it needs to generally dissolve into tissue (muscle) so it needs to distribute out of the blood to have its e that is based on solubility. Not so much in water but the distrubition point in tissu If its really soluble in water, then it won't be very soluble in tissues (not just water solubility). We don't want it to stay in the body for ever, so the last process is elimination (thr urine, or secondary through the liver) and often things metabolised by the liver ar removed through urine. Critically based on dissolution (the better a drug will diss the more effective it will be eliminated).

Developed By Nabil Edelbi The more a drug will dissolve the more likely it will be removed from the body.It is critical for therpectics and our understanding. Its not only taking a. tablet that matters.

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Oral, buccal and inhalations (Methods that go through the mouth - Oral: Swallowing (tablets or mixtures). - Buccal: Refers to the dosage forms that are kept within the mou complete their action there (lozenges, gargles) Inhalation: Into the mouth, intended to go the lungs (normally fo but being trialled for other types of diseases). Opthalmic (Things that go into the eye): Drops, ointment, eye w Aural (In the ear): ear drops. Interaaterial (injection into the artieries) not very common, reaso difficult and painful. Topical (goes on the skin): ointments, creams, lotion, patches. Veginal,rectal and intra-urethral: treatment of infections that are although rectal can be used as an alternative to oral for patients w swallow or patients that are unconscious or vomiting. Intravenous (Into the veins), intarmuscular (into the muscles) an subcutaneous (directly under the skin but not into muscles). Intraspinal: directly into the spine. Intra-articular: into joints, usually for local effect. Nasal: Nose drops or nasal sprays, local treatment. Into a form fo diseases.

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Ones requiring disollution: -intavenous, intraarterial and intraspinal drugs need to be dissolv undissolved can a high potential for danger towards the patient i small particles could block a capilary thus must be dissolved. -Eye drops (solutions) require undissolved particles. Topical treatments (two main reasons include to have an effect lo that point --> rash or an infection and want to treat the skin its se don't then want it to go to the rest of the body ideally staying at t and prevent unwanted side effects thus understanding the dissolu the skin and its solulbility in the layers of the skin are important. require the movement into the blood stream and thus need to circ dissolve across the skin. -Intramusclar: we don't want these to be solutions and rather be undissolved material in them can be used for depo injections (inj into the muscle staying there for a long time and grudually releas amount over a period of time, not requiring injections very often enough drug will dissolve into the tissue) includes subcutaneous extent.

Developed By Nabil Edelbi

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Phenytoin

Hence there are no situation where dissolution isn't important, ho when deleriying to a drug to a patient, you will need to understan something about how fast and how it dissolves and how much it dissolve and what solvents it will dissolve into. in order to optim preformance of that formulation. Hence it is very important!

Griseofulvin 4

ENTHALPY

H

ENTROPY

S

FREE ENERGY

G

Enthalpy ∆H is a measure of heat absorbed during a process. (Chemical or Physical). Entropy ∆S is a measure of disorder introduced during the process.

Phenytoin (Dilantin) used for patients with epalicy, not as widely u anymore but still contain patients taking it (Newer medicine that w At one point changed the formulation by a little bit. Doctors starte overdoses with patients showing signs although the prescription h changed. Very confusing a change in the formulation resulted in b dissolution and a result patients were essentially getting more of th even though the dose had not change. Toxicity resulted from a cha formulation which increased dissolution. Patients would still get th amount but required less dosage.

Grseofulvin (Grisovin): Anti fungal agent, not very soluble thus har it to dissolve in the gastointesential tract. Quiet soluble in fat and lip

Free energy ∆G is a measure of spontaeity of a process.

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recommended to be taken by food. Amount absorbed increased by t presence of a fatty meal because is fat soluble.

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FOR A PROCESS H

<

0

means

Exothermic

H

>

0

means

Endothermic

S

<

0

means

Increase in-order.

S

>

0

means

Increased Disorder.

G

<

0

means

G

>

0

means

Forward process is spontaneous. Forward process is not spontaneous and reverse process will be spontaneous if poss

Ice melting: ∆H is positive as an input of temperature is required. ∆S would be positive as this is an increase of disorder. ∆G depending on the temperature if at -20 would be greater than 0, if temperature is +20 then ∆G would be spontaneous.

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G = H - TS

Ice would be the opposite.

G < 0 G > 0 G < 0 G > 0

Developed By Nabil Edelbi

Spontaneous Not spontaneous

solutes dissolve Solutes do not dissolve.

Special change for this reaction when all reactants and products are in their standard states.

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G° =

-RTlnKEQ

System is at equilibrium!

G° is the free energy change for the reaction when all reactants and products are in their standard states

G

=

G° + RTlnQ

∆G is the free energy change for every other conditions and their reactants and products are not in their standard states. where Q is the reaction quotient (Like the equilibrium constant but when a reaction has not yet reached equilibrium).

G is the free energy change for the reaction when all the reactants and products are not in their standard states, and Q is the reaction quotient

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Are an artefact, designed to make the mathematics much easier, set up by convention and differ b in solutes in dilute solution, gases, solvents, pure liquids and solids, solutes in non-dilute solution Have one very obvious consistenty, consisting of all 1.

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STANDARD STATES By convention:

There for the mathematcs but not for importance.

* solutes in dilute solution * gases * solvents * pure liquids and solids * solutes in non-dilute solutions H°

concentration pressure mole fraction mole fraction mole fraction

S°

= = = = =

Mole fraction--> the fraction of the mixture composed by that particular item.

1M 1 atm 1 1 1

G°

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ACTIVITY = a a a

= = =

effective concentration

C P x

for for for

Generic term, allows multiply and divide numbers that we cou never do, so instead of using three different values, we use the activity. This covers concentration, pressure and mole fraction (relates to standard states). We do not talk about concentration and define them in terms o activity, there is no units.

solutes gases sovents, solids and liquids.

C= numerically equal to the. molar concentration (Only works if it is moles per litre). P= for a gas is its pressure in atmosphere. X= mole fraction for solvents, solids and liquids, you o take the number and dispose of the unit (needs to be mo per unit). Activity is unitless.

Activity has NO UNITS.

Developed By Nabil Edelbi

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A

+

B

KEQ =



C

+

D

activity of the products (CxD) __________________________ activity of the reactants (AxB)

No longer defined solely in terms of concentrations but now defined in ac that allow gases and solids that normally cannot be defined in terms of concentrations (Concentrations of moles per litre is one component but wo very useful allowing to look more broadly.

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AS

+

B AQ



0.08M KEQ = =

C AQ

+

DG

0.035M 0.048 atm

0.035 x 0.048 _____________. (MAKE SURE THEY ARE IN THE RIGHT UNITS!) 1 x 0.08 0.021

No units for the final answer

Solids have a mole fraction of 1

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∆G and ∆G˚ tell us something about equilibrium, there values tell us something is useful, rather the position of the equilibrium and direction. ∆G˚ is the position. ∆G is the direction to reach equilibrium.

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G°

where equilibrium IS

If G°

<

0

equilibrium lies

If G°

>

0

equilibrium lies

Left

If G°

=

0

equilibrium lies

Equilibrium is in the middle (K=1).

Broad range of solubilities.

Right

It is a constant

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G

how to get there

If G

<

0

reaction goes

Forward

to equilibrium

If G

>

0

reaction goes

Backwards

to equilibrium

If G

=

0

reaction



0, the reaction proceeds in the appropriate direction until

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If

G

* * * then

Tell you to go forwards or backwards

equilibrium

is at EQUILBRIUM.

Developed By Nabil Edelbi

Equilibrium is reached. ∆G=0 Q (non equilibrium conditions) =Keq (at equilibrium). It is only true when at equilibrium.

G = G° + RTlnQ becomes

∆G˚=-RTlnKeq

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G

=

G° + RTlnQ

(i)

At equilibrium Q=Keq ∆G=0 0=∆G˚ + RTlnKeq ∆G˚=-RTlnKeq

Only at equilibrium!

Tease out th implication doesn't equ zero, the rea will go in th will go, spontaneou the three fa

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(ii)

Not at equilibrium Q doesn't equal ∆G doesn't equal 0 ∆G = ∆G˚ + RTlnQ

(iii)

Q = 1 (rare)

Rare doesn't usually happen where Q=1 ∆G=∆G˚ + RTln1 ∆G=∆G˚ Mathematically happens but it is not an equilibrium system.

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FDP



G3P

+

DHAP

G° at 37°C = 23.1 kJ/mol Let [FDP] = 0.02M, [G3P] = 0.01M, [DHAP] = 1 x 10 -6M * calculate the value of K EQ * in which direction is this reaction proceeding? KEQ

Direction

Developed By Nabil Edelbi

∆G˚=0 When Keq=1 and the concentrations of products and reactants are the same.

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Developed By Nabil Edelbi

Developed By Nabil Edelbi

Since temperature effects equilibrium constants and hence also effects ∆G˚. The relationship is made by the Vain't Hoff Isochore (VHI)

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G° = =

H°

-

TS°

not.a very useful parameter thus ∆H˚ is more useful

-RTlnKEQ

S is a constant that doesn't change with temperature. R is a gas law constant. So these terms don't change with temperature.

Therefore lnKEQ =

S° R

-

H° RT This term does change with temperature.

or lnKEQ =

- H° + constant RT

van’t Hoff isochore 19

lnK1 = K2

-H° ( 1 R T1

R

=

8.314 x 10 kJ/K/mol By Nabil Edelbi Developed

=

8.314 J/K/mol

-3

1 ) T2

More useful when we have three of the four values then we can calculate the forth.

Gas constant!

Use the first as the ∆H˚ is in kj!

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At 298K, K EQ = 0.135 and at 323K, K EQ = 2.68 Calculate H°, S° and G° at both temperatures.

∆H˚ and ∆S˚ are independent of temperature. and thus there will be two ∆G˚ Values ∆S˚ Should be the same for both temperature!Equilbrium constant that we are interested in.

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Developed By Nabil Edelbi

Developed By Nabil Edelbi

Developed By Nabil Edelbi

Now we will join everything we have learnt and see its effect on solubility.

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The van’t Hoff isochore describes the effect of temperature on EQUILIBRIUM CONSTANTS. Any type of equilibrium constant can be used in the van’t Hoff isocho 22

Vaporisation/condensation equilibrium A LIQUID

A VAPOUR

K EQ =

aVAPOUR a LIQUID

=

PVAPOUR 1

=

PVAPOUR

ln P 2 = P1

Shows how equilbriums can be simplified. Pure liquids have a mole fraction of one. This is not a general result and occurs when it is derived from that equilbrium. Only applies to the vapourisation of a luquid. It shows you the atmostpheric effect of temperature on boiling point.

-H° VAP ( 1 - 1 ) R T2 T1

Developed By Nabil Edelbi

Clausius Clapeyron equation

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Just dissolves and doesn't form ions (dissociate)

Dissolution of drugs which do not dissociate in solution A SOLID K EQ = = ln S 2 = S1

+

H 2OLIQUID

A SOLUTION

aSOLUTION X 1 1 X 1 solubility -H° SOL ( 1 - 1 ) R T2 T1

+

H 2OSOLVENT

Fudging a little as we have two products on the right side. Providing that dilute -> not very soluble, thus the vast majority are solvent compared to the solution.

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Solubility of nonionic solute at

25°C is 0.0165M 45°C is 0.0754M

Calculate H°SOL

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Dissolution of drugs which do dissociate in solution (monovalent) ABSOLID KEQ

+

A+AQ + B - AQ + H 2OSOLVENT

H 2OLIQUID =

a A+ x a B- x 1 1 x1

=

[A +][B -]

only + and - otherwise it will become too complex! There also only has to be equal of the two ions as each solid forms one ion each.

= K Developed By Nabil Edelbi SP

=

S2

For solutes that do dissolve into solution, the EQ is the K.

Because solubility of AB is S moles/litre S moles of AB produce S moles of A+ and S moles of B-, therefore concentration of both A and B is S.

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Solubility of (monovalent) ionic solute at 20°C is 0.00289M H° SOL = 42.6 kJ/mol Calculate the solubility at 50°C

In All the examples we have been looking at the ∆H˚ has been positive, what this means that, the dissolution process is essentially an endothermic (heat needs to be taken in) hence solubility will increase as temperature is increased. This is the case for the vast majority of solutes, but there are a small amount that dissolve in a exothermic fashion (fizz in water when dissolving, or go cold when dissolving, they will have a negative value for ∆H˚ and hence solubility will decrease with an increase in temperature. This is important to know because there are number of pharmaceutical compounds that if you want to dissolve them, if you heat them up they will cause problems as they are exothermic in their solubility, in their dissolution and need to know that by adding ice to the water that will cool it down so the product will dissolve.

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Developed By Nabil Edelbi

Developed By Nabil Edelbi

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Acid

Base

H+

+

Acidic DRUG loses proton to form charged H+

HA

+

pH only affects the drugs that are acids and bases and the effect of pH is the effect of ionisation mediated of the loss or gain of a proton from an acidic or basic molecule. Anion

A-

Basic DRUG gains proton to form charged cation B

+

H+

HB +

DRUG classified by whether its neutral form

can gain or lose a proton.

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HA acid

H+

HB+ conjugate acid

H+

ACIDIC form

+

+

Aconjugate base B base

For an acid it is there naturally for a base you need to add it on. on the left hand side is the acidic form, on the right side is the basic form, may or may not be ionised (may or may not have the ion) We only talk about acid dissociation in pharmacy, never talk about base dissociation in pharmacy.

BASIC form Developed By Nabil Edelbi

When considering acid/base equilibria, ALWAYS refer to the reaction where proton lost from acidic form - either from the neutral form of an acidic drug or from the charged form of the conjugate acid of a basic drug. Start with proton attached, and draw equilibrium as loss of proton. 29

Acid dissociation constant Ka Ka

=

[H +][basic form] [acidic form]

=

[H +][A- ] [HA]

or

[H +][B] [HB +]

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Henderson-Hasselbalch equation pH

=

pKa

+

log [basic form] [acidic form]

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ACIDIC drug H + + A-

HA

BASIC drug HB+

pH < pK a [H ] > K a mostly HA acidic form no ionised - attached proton [H+ ] > Ka mostly HB+ form Acidic ionised - Yes proton Attached +

H+ + B

pH > pK a [H ] < Ka mostly Aform basic ionised - Yes proton Removed [H+]< Ka mostly B form basic ionised - n...