Specialized cells in GI tract \ PHAGOCYTOSIS transport sub-micron size insoluble particles Bypass blood/liver LIMITED CAPACITY need enough drug to have efficacy, so typically would not bring in enough. --\> enter some infectious agents

When the soulubility limit is EXCEEDED solulte will spontaneously PRECIPITATE out of solution Not instantaneous persists for a period of time needs a seed --\> nucleation Factors that inhibit diffusion (inhibit aggregation - viscosity low temperature

LOW SOLUBILITY LOW PERMEABILITY taxol

1. Remove molecule from the crystal lattice (disruption of solid mass) 1. REQUIRES WORK ++ 2. Cavity must be created (HOLE) 1. REQUIRES WORK ++ 3. Dissolving solute molecule Moves into the cavity and interacts with the solvent (INSERTING) 1. _LOSES WORK ---_ 1. __-n x work \ \ Dissolution occurs as long as the SUM is \<0

Solubility 1/2 Flashcards by Karlo Sison

Rare Exceptions to solubility

Chemically “inert” nanoparticals
- gold
  - Carrier for chemically insoluble drugs
  - Imaging agents
- silver
  - antimicrobial agent
Insoluble Particles
- Dimensions mimicking rod-shaped bacteria (1x5um)
  - local irritation / tissue dmg when into the lung
  - carcinogen = exposure is chronic
- Silica/carbon/asbestos
**SIZE MATTERS

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M-cells

Specialized cells in GI tract
- *PHAGOCYTOSIS
- transport sub-micron size insoluble particles
Bypass blood/liver
LIMITED CAPACITY
- need enough drug to have efficacy, so typically would not bring in enough.
–> enter some infectious agents

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Water Solubility is….

The key to success delivery of more than 99% of medicines in use.

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Supersaturation

When the soulubility limit is EXCEEDED
- solulte will spontaneously PRECIPITATE out of solution
Not instantaneous
- persists for a period of time
  - needs a seed –> nucleation
Factors that inhibit diffusion (inhibit aggregation
- - viscosity
- low temperature

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Maximum equilibrium solubility

*Under EQ, 2 process happening at same time

Rate of dissolution of the solute from a suspension of a undissolved particles of the solute in the solution is

the rate of precipitation and deposition of solute from the solution BACK onto solid particles of the solute suspended in the solvent

*LARGER PARTICALS => Grow at the expense of smaller paticles due to surface area

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Non-electrolyte Solution

No ions are formed on dissolution in water

does not increase electrical conductivity of the solution

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Electrolyte Solutions

Ions are formed upon dissolution in water

increases electrical conductivity

Strong
- Dissociate completely
- HCl / Na2So4
Weak
- Partial dissociation
- CO2, phenobarb, ephedrine <2

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BCS

Definition of HIGHLY SOLUBLE

1 dose (highest available stength)

will dissolve completely in 250ml of water

between ph 1 - 7.5

**dose, not weight (as in USP)

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BCS Class 1

High Solubility

High Permeability

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BCS Class 2

LOW SOLUBILITY

High Permeability

*phenytoin

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BCS

Class 3

High Solubility

LOW PERMEABILITY

cimetidine

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BCS

Class 4

LOW SOLUBILITY*
LOW PERMEABILITY*

taxol

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Colloidal Dispersions

(nanosuspensions)

*NOT SOLUTIONS

Consist of small particles ranging between

1-~500nm

(egg white/jelly/blood plasma)

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Coarse Dispersions

*NOT SOLUTIONS

Consist of particles LARGER than

~0.5um =

~500nm =

~500 Angstroms

suspensions that need to be shaken / sand&water / RBC in plasma

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Forces Affecting Solubility

Cohesion
- Attraction of like molecules (like dissolves like)
Adhesion
- Attraction of UNLIKE molecules
  - Dipole moments
    - Reduce entropy / impose structure in liquids
  - Ion-dipole iteractions
    - enhance solubility of ionic species in solvents w/ larger dipole moments
  - Hydrogen bonds
    - enhance local structure formation in solvents w/ larger dipole moments

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Steps to DISSOLUTION

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Remove molecule from the crystal lattice (disruption of solid mass)
1. REQUIRES WORK ++
Cavity must be created (HOLE)
1. REQUIRES WORK ++
Dissolving solute molecule Moves into the cavity and interacts with the solvent (INSERTING)
1. LOSES WORK —
  1. -n x work

**Dissolution occurs as long as the SUM is <0

Indicators of Molecular Cohesion

between solute molecules

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The Boiling Point of liquids

melting point or glass transition of solids

INCREASE Phase transition temp –> DECREASE solubility

Hydration of Ions

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Size and Charge Matter!

may have opposing effects on solubility

Hydrophobic Hydration

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Nonpolar portions of solute molecules have a high structure

INDUCING EFFECT

REDUCES the entropy of the solution

**due to water “cage” reduces entropy

Common Ion Effect

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Use of a different salt form

Increases the apparent solubility

observed for hcl salts of some weakly basic drugs

Salting OUT

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Adding excipient salts w/ small cations / small anions (NaCl)

to solutions of drugs that dissociate in water to form saltes

—> REDUCE THE SOLUBILITY OF THE DRUG SALT

Salting In

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Addition of excipient salts w/ LARGE cations or Large anions (p-touelenesulfonate)

INCREASE the solubility of drug salt

pH = pKa

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50% of the drug is ionized

so….

S_total= 2S_o

S_total=S_o+[Concentration of ionized species]

S_o=solubility of UNIONIZED form

Amphoteric Substances

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Drugs are both weakly basic / acidic

there exist a pH where the net charge is ZERO

= Isoelectric point

@isoelectric point solubiity is MINUMUM

Determining pKa using solubility data

\*for poorly soluble drugs that are weak acids/bases you can estimate pKa **When pH is @ 2 x (solubility of unionized form S_o)** **ph = pKa**

Solubility changes by a Factor of 10 when....

\*in pH regions where most of the drug is IONIZED... **Changing the pH by 1** --\> solubility changes by a factor of 10! \*unless ionized form is exceeded. \*\*\*adjusting pH to favor formation of an ionized form is a great way to increase solubility of an ionizable drug

Water as a Solvent

* Polar Solvant * **High** dielectric constant = 80 * *~modest* dipole moment =1.84 debye units * **High** hildebrand solubility parameter * 23cal^1/2cm^-3/2, related to solvent's cohesive e- density * measure of how difficult it is to remove a molecule of solvent by vaporization from the bulk solvent

**Non-Polar Solvents**

* **Benzane** * Dielectric constant = 2 & 0 dipole moment * **Hexane** * Dielectric constant = 2 & 0 dipole moment * **CO2** * Dielectric constant = 1.6 & 0 dipole moment

Solvents w/ INTERMEDIATE polarity

* **Ethanol / Isopropanol / Acetone** * miscible with BOTH polar and non-polar solvents * have intermediate dielectric constants/dipole moments / hildebrand solubility parameters * \*used to wash away spills, since it should be able to dissolve most things

Aqueous Co-solvents

* Solvents of **intermediate polarity** * ethanol/glycerol/ propylene glycol, polyoxethylene glycos * Mixed w/ Water to solubize poorly soluble non-polar drug substances * **\*NONLINEAR / NONIDEAL** * hard to predict the solubility * **BEWARE OF TOXICITY ISSUES** * ****percipitation can form * Metabolic products of ethylene glycols * prefer propylene glycol

**Complexation**

Co-solutes that interact w/ poorly soluble solutes form complexes --\>**ENHANCES Solubility** of poorly soluble solutes if the complex itself has high h2o solubility ex. cyclodextrins / serum albumin (acts as a carrier) * ~slow rate of administration needed to allow for drug to form complex with serum albumin*

Shake-flask Method

Used to measure **Octonal-water partition coefficients** 1. Mix Octanol / Water 2. Known amount of drug added -\> shaken vigorously 3. Phases are allowed to seperate 1. Drug is measured in each phase

Half-Maximal Partitioning for **Weak Acids** (ph~5)

50% of maximum partitioning occurs at this pH pH = pKa **+** logP (octonal/water) **PLUS** This is how drugs are mostly ionized @ intestines @pH of 6-7, and are readily absorbed through lipid membranes

Half-maximal partitioning for **Weak Bases**

50% of maximum partitioning occurs at this pH pH = pKa - logP (octonal/water) **MINUS**

Maximum Partitioning for **Amphoteric Compounds**

Maximum partitioning into octonol occurs at **Isoelectric Point**

Cohesion

Attraction of **LIKE** molecules ## Footnote **LIKE DISSOLVES LIKE**

Adhesion

Attraction of **UNLIKE** molecules * _Dipole moments_ * Reduce entropy / impose structure in liquids * _Ion-dipole iteractions_ * enhance solubility of ionic species in solvents w/ larger dipole moments * _Hydrogen bonds_ * enhance local structure formation in solvents w/ larger dipole moments

Supersaturated Solution

Precipitation of excess solute requires a triggering event (**NUCLEATION)** When **MAXIMUM** equilibrium amount of solute is dissolved in a soleunt.

Solubility 1/2 Flashcards

(38 cards)