Solutions And Solubility

Question 1

Extemporaneous formulation (example)

Answer 1

Thiamine (vitamin B1) HCL oral liquid
Medium therapeutic index
Moderate technical risk
Therefore a low to moderate risk extemporaneous preparation

Question 2

Extemporaneous formulation (example)
Clinical pharmaceutics

Answer 2

Drug should be in solution at all strengths (usually 20-100mg/ml)
pH sensitive: specification of ingredients should be checked prior to use
Stability depends on excipients

Question 3

Optimising solubility (like dissolves like)

Answer 3

Acyclovir (aciclovir)
Max solubility in water at 25 degrees exceeds 100mg/ml
At physiological ph acyclovir will exist as unionised form (Mr 225) and a max solubility in water at 37 degrees of 2.5 mg/ml
pH affects solubility and the salt form

Question 4

What are the pKas of acyclovir

Answer 4

2.27 and 9.25

Question 5

What is the ClogP of acyclovir

Answer 5

-0.95

Question 6

4 types of solutions

Answer 6

Oral solution
Oral elixirs (contain ethyl various alcohols as co solvent. Phenobarbital elixir, 10% v/v propylene glycol, 20% v/v ethyl alcohol)
Oral syrups (ca. 85% sugars)
Others eg mouthwashes, gargles, rectal solutions and enemas

Question 7

Define pharmaceutical oral solutions

Answer 7

Liquid preparations in which the therapeutic agent and the various excipients are dissolved in the chosen solvent system

Question 8

Advantages of oral solutions

Answer 8

Ease of use (children or elderly)
Drug is dissolved and readily available for absorption (as long as the drug is soluble at stomach/GI pH it will have a greater bioavailability than solid oral dosage forms
Modification of taste can improve compliance of bitter tasting drugs

Question 9

Disadvantages of oral solutions

Answer 9

Stability - can’t be used for drugs unstable in water e.g. Aspirin
Limited by the solubility of some drugs
Expensive to transport compared to some other dosage forms (adds to overall cost)
Bulky for patients to carry with them

Question 10

Common excipients

Answer 10

Flavours and colours - sweeteners,dyes, etc.
Preservatives including antioxidants
Vehicle - usually purified water
Co solvents A ethanol, propylene glycol, glycerin
Solubility enhancing agents - ie surfactants
Viscosity modifiers
Buffers

Question 11

Removal of a molecule or an atom from the solid state

Answer 11

Formation of a cavity within the solvent - energetically unfavourable as disorder in the matrix increases and there are fewer solvent-solvent interactions
Solute separation from bulk solute - solute-solute interactions are unfavourable but it is entropically viable
Accommodation of the drug molecule into the cavity - the results of favoured solvent-solute interactions which are similar to solvent-solvent interactions (like dissolves like e.g. Polarity)

Question 12

Drug solubility and dissolution

Answer 12

Involved endothermic processes (requires absorption of heat, breakage of solute-solute and solvent-solvent bonds, formation of solute-solvent bonds)
May liberate energy: dissolution occurs when the Gibbs free energy is negative

Question 13

Legal requirements of drug solubility

Answer 13

Drugs and excipients of a solution must be and remain in solution throughout the shelf life of the product
Products are homogenous (uniform)

Question 14

What causes changes in solubility

Answer 14

Changes in pH and or temperature presents challenges to maintaining homogeneity

Question 15

Solubility at the selected pH may be

Answer 15

High - stable, easy to formulate
Moderate - maybe be pH sensitive for example consider using solubility enhancers as co solvents, buffers or surfactants
Low - co solvents and similar approaches do not exchange solubility sufficiently, consider alternative formulations such as suspensions

Question 16

Very soluble - approx volume of solvent ml per gram of solute

Answer 16

<1

Question 17

Freely soluble - approx volume of solvent ml per gram of solute

Answer 17

From 1 to 10

Question 18

Sparingly soluble - approx volume of solvent ml per gram of solute

Answer 18

From 30 to 100

Question 19

Very slightly soluble - approx volume of solvent ml per gram of solute

Answer 19

From 1000 to 10000

Question 20

Practically insoluble

Answer 20

> 10000

Question 21

Factors affecting solubility

Answer 21

Crystal form
As melting point increases solubility decreases
Chemical factors - substituent type and position
pH will affect the solubility of acids and bases:
- at pH values above pKa the solubility of acidic drugs increases
- at pH values believe pKa the solubility of basic drugs increases
Acid + bases = salt + water
Zwitterions behave as acids at basic pH and bases at acidic pH

Question 22

Polymorphism

Answer 22

Ritonavir (antiviral)
2 forms - active and inactive
Presence of the inactive form in the active form will instigate a reaction which results in all active forms converting to the inactive form - lower energy state so this may occur spontaneously

Ranitidine (Zantac) - H2 receptor antagonist

Paracetamol - stable form I monoclinic
Metastable form II orthorhombic
Unstable form III

Cortisone acetate - 5 different polymorphs, four of which are unstable in water and change to a stable form

Question 23

Optimising solubility (like dissolves like)

Answer 23

Salt form - salts are often more water soluble than free acids/bases and are usually more stable. Salt form is part of the drug (e.g. Lidocaine HCL not lidocaine)
Modify pH so the salt form and ionised form predominates and solubility is increased. pH may be controlled with a buffer
Co solvents improve solubility for chemicals with poor aq solubility but offer issues wth toxicity which limit use. Complex and difficult to determine optimum properties of mixtures

Question 24

Drug - erythromycin
Aqueous solubility -
Solubility in non aqueous solvent -
Form -

Answer 24

Aqueous solubility - slightly soluble
Solubility in non aqueous solvent - soluble
Form - tablets

Question 25

Drug - ibuprofen Aqueous solubility - Solubility in non aqueous solvent - Form -

Answer 25

Aqueous solubility - practically soluble Solubility in non aqueous solvent - freely soluble Form - oral suspension, tablets, cream, gel

Question 26

Drug - amoxicillin sodium Aqueous solubility - Solubility in non aqueous solvent - Form -

Answer 26

Aqueous solubility - very soluble Solubility in non aqueous solvent - sparingly soluble Form - injection

Question 27

Drug - amoxicillin trihydrate Aqueous solubility - Solubility in non aqueous solvent - Form -

Answer 27

Aqueous solubility - slightly soluble Solubility in non aqueous solvent - very slights soluble Form - oral suspension, capsule

Question 28

Excipients for pharmaceutical oral solutions

Answer 28

``` The aqueous vehicle Co solvents Buffers Sweetening agents viscosity modifiers Antioxidants Preservatives Flavours and colours ```

Question 29

Example of aqueous vehicle excipients

Answer 29

Purified water BP or USP Prepared by distillation, ion exchange or reverse osmosis Solid residue should be less than 1mg per 100ml Not to be used for parenteral formulation (use water for injections BP for this instead) Not tap water as it isn't purified

Question 30

Examples of co solvent excipients

Answer 30

Glycerol (glycerin) - miscible in water. Similar effects to ethanol co solvent Alcohol USP (CH3CH2OH) - 94.9 -96% v/v ethyl alcohol (ethanol). Co solvent or single solvent. Toxic Propylene glycol USP - odourless and colourless fool often used as a replacement for glycerol Polyethylene glycol (PEG) - polymer of ethylene oxide monomers with terminal OH groups. Exact specifications depends on the number of repeating units and MW. Different grades such as PEG 200/400, different properties so different grades used for different chemicals Surfactants - depends on the critical micelle conc of a drug Complex calixarenes and cyclodextrins

Question 31

Examples of buffer excipients

Answer 31

Control pH Enhance stability Buffers should not work in the formulation but not necessarily in the body Examples - phosphate buffered saline pH 7-7.4 (sodium phosphate/ disodium phosphate, 0.8-2%) - citrate (Na-citrate, citric acid, 1-5%) - acetates (Na-acetate, acetic acid, 1-2%)

Question 32

Sweetening agents excipients

Answer 32

Increases compliance of product Examples: sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium, aspartame Avoid use of sugar in patients with diabetes mellitus

Question 33

Viscosity modifier excipient examples

Answer 33

Product must easily be poured Examples: non ionic cellulose derivatives (methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose) Polyvinylpyrrolidone Ionic polymers (sodium carboxymethylcellulose - anionic, sodium alginate - anionic, polymethylvinylether-maleic anhydride)

Question 34

Antioxidants excipient examples

Answer 34

Increase stability of drugs which may degrade by chemical oxidation by inhibition of the initiation and or propagation of free radical generating chain reactions caused by presence of O2 ( e.g. Opiates) Examples: sodium sulphite, metabisulphites, formaladehyde, ascorbic acid, butylated hydroxyanisole (BHA) and BHT in more lipid rich formulations Used in low conc May be used in conjunction with chelating agents which will complex with metal ions

Question 35

Preservatives excipients examples

Answer 35

To control the microbial load Ina. Formulation which should be kept below the min inhibitory conc Require broad spectum antimicrobial activity (gram +ve/-ve, fungi) Low toxicity Examples: paraben, sodium benzoate/ benzoic acid