Solutions And Solubility Flashcards
Extemporaneous formulation (example)
Thiamine (vitamin B1) HCL oral liquid
Medium therapeutic index
Moderate technical risk
Therefore a low to moderate risk extemporaneous preparation
Extemporaneous formulation (example) Clinical pharmaceutics
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
Optimising solubility (like dissolves like)
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
What are the pKas of acyclovir
2.27 and 9.25
What is the ClogP of acyclovir
-0.95
4 types of solutions
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
Define pharmaceutical oral solutions
Liquid preparations in which the therapeutic agent and the various excipients are dissolved in the chosen solvent system
Advantages of oral solutions
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
Disadvantages of oral solutions
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
Common excipients
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
Removal of a molecule or an atom from the solid state
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)
Drug solubility and dissolution
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
Legal requirements of drug solubility
Drugs and excipients of a solution must be and remain in solution throughout the shelf life of the product
Products are homogenous (uniform)
What causes changes in solubility
Changes in pH and or temperature presents challenges to maintaining homogeneity
Solubility at the selected pH may be
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
Very soluble - approx volume of solvent ml per gram of solute
<1
Freely soluble - approx volume of solvent ml per gram of solute
From 1 to 10
Sparingly soluble - approx volume of solvent ml per gram of solute
From 30 to 100
Very slightly soluble - approx volume of solvent ml per gram of solute
From 1000 to 10000
Practically insoluble
> 10000
Factors affecting solubility
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
Polymorphism
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
Optimising solubility (like dissolves like)
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
Drug - erythromycin
Aqueous solubility -
Solubility in non aqueous solvent -
Form -
Aqueous solubility - slightly soluble
Solubility in non aqueous solvent - soluble
Form - tablets
Drug - ibuprofen
Aqueous solubility -
Solubility in non aqueous solvent -
Form -
Aqueous solubility - practically soluble
Solubility in non aqueous solvent - freely soluble
Form - oral suspension, tablets, cream, gel
Drug - amoxicillin sodium
Aqueous solubility -
Solubility in non aqueous solvent -
Form -
Aqueous solubility - very soluble
Solubility in non aqueous solvent - sparingly soluble
Form - injection
Drug - amoxicillin trihydrate
Aqueous solubility -
Solubility in non aqueous solvent -
Form -
Aqueous solubility - slightly soluble
Solubility in non aqueous solvent - very slights soluble
Form - oral suspension, capsule
Excipients for pharmaceutical oral solutions
The aqueous vehicle Co solvents Buffers Sweetening agents viscosity modifiers Antioxidants Preservatives Flavours and colours
Example of aqueous vehicle excipients
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
Examples of co solvent excipients
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
Examples of buffer excipients
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%)
Sweetening agents excipients
Increases compliance of product
Examples: sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium, aspartame
Avoid use of sugar in patients with diabetes mellitus
Viscosity modifier excipient examples
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)
Antioxidants excipient examples
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
Preservatives excipients examples
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
