1. Why Do We Need to Know Drug Solubility?
1.1. Compounding/Proudction
1.1.1. Shelf Life
1.1.2. Drug Stability
1.1.3. Drug Saturation pH
1.1.3.1. Desired lower than drug saturation pH
1.1.3.2. Avoid precipitation
1.2. Absorption and Elimination
1.2.1. Solubility varies in biological fluids
1.2.2. Dispersion
1.2.2.1. Drug Particles must be dispersed to be well absorbed
1.2.2.2. Drug to be dispersed to go through systemic circulation
1.2.3. Drugs of Low pH
1.2.3.1. formulation changes to accommodate
1.2.3.2. Uses cosolvents
2. Dissolution Rate
2.1. In Vitro
2.1.1. Temperature Changes
2.2. In Vivo
2.2.1. Agitation
2.2.1.1. Decreases h
2.2.2. Increase Viscosity
2.2.2.1. Makes diffusion layer thicker and increases h
2.2.3. High Cs, Low Ct
2.2.3.1. Salt form
2.2.3.2. pH of media
2.2.3.3. Cosolvent
2.3. Determined by:
2.3.1. Solubility
2.3.2. Permeability
2.4. Noye's Whitney Equation
2.4.1. Tells us dissolution rate
2.4.2. Smaller particle size increases dissolution rate
3. Improvement Of...
3.1. pH Adjustment
3.1.1. Route of Administration
3.1.1.1. Drug Salt form allows for adjustment of concentrations for solubilization
3.1.1.1.1. Drug Salts quickly ionize
3.1.1.1.2. Drug salts disassociates quickly in water
3.1.2. Drug Stability
3.1.2.1. pH adjustment determines if drug is ionized or not which could increase or decrease solubility
3.1.3. Drug pKA
3.1.3.1. pH=pKA drug is 50% ionized
3.1.3.2. Adjusting pH could increased or decrease how ionized a drug is which impacts solubility
4. Formulation of Oral Solutions
4.1. Cosolvents
4.1.1. Alcohol
4.1.1.1. Most popular
4.1.1.2. Dissolves hydrophobic drug
4.1.1.3. Limits on how much you can use
4.1.1.3.1. In children
4.1.1.3.2. OTC products
4.1.1.3.3. Adverse effects on CNS
4.1.2. Glycerol
4.1.2.1. Sweet liquid
4.1.2.2. Miscible with water
4.1.3. Propylene Glycol
4.1.3.1. dissolves hydrophobic drugs
4.1.3.2. Colorless/odorless
4.1.3.3. High levels contraindcated in patients younger than 4
4.1.4. Enhances Drug Solubility
4.1.5. Precipitation possible if cosolvents are added too quickly to aqueous
4.2. Preservatives: Included to retard microbial growth in drug medium/vehicle
4.2.1. Alcohol
4.2.1.1. Commonly used at 15% concentrations
4.2.2. Benzoic Acid/Sodium Benzoate
4.2.2.1. pH <5
4.2.2.2. Water soluble
4.2.2.3. pH dependent solubility
4.2.3. Propylene Glycol ~10%
4.2.3.1. Commonly used at 10% concentrations
4.2.4. Parabens
4.2.4.1. Methylparaben
4.2.4.2. Propylbaraben
4.3. Sweeteners
4.3.1. Added to improve palatability of a drug
4.3.1.1. Geriatrics
4.3.1.1.1. Coffee
4.3.1.1.2. Licorice
4.3.1.2. Pediatrics
4.3.1.2.1. Bubblegum
4.3.1.2.2. Berries
4.3.2. Natural
4.3.2.1. Sucrose
4.3.2.1.1. High amounts avoided in diabetic patients
4.3.2.1.2. Avoided in patients with hereditary fructose intolerance
4.3.2.2. Sorbitol
4.3.2.2.1. Laxative effect if not diluted
4.3.2.2.2. Preservatives are required if concentration is less than 70%
4.3.2.2.3. Okay to use in diabetic patients (Same with Dextrose)
4.3.2.2.4. Contraindicated in patients with hereditary fructose intolerance
4.3.2.3. Mannitol
4.3.3. Artificial
4.3.3.1. Saccharin
4.3.3.2. Aspartame
4.3.3.2.1. 150-200 times as sweet as sucrose
4.3.3.2.2. Caution for use in patients with headaches/migraines
4.3.4. Miscellaneous Diabetic Syrups
4.3.4.1. Methylcellulose
4.3.4.2. Hydroxyethyl Cellulose
4.3.4.3. Sodium CMC
4.3.4.4. Saccharin and Aspartame
4.3.4.4.1. Can be added to improve palatability
4.3.4.4.2. Bitter aftertaste
4.4. Coloring Agents
4.4.1. Makes product more attractive
4.4.2. Color chosen matches flavor of product
4.4.3. Azo dyes are yellow/sunset
4.4.4. Quinolone dyes are yellow
4.4.5. Coloring agents have been associated with hypersensitivity reactions
4.5. Antioxidants
4.5.1. Some drugs can be oxidized so antioxidants are necessary (epinephrine)
4.5.2. Ascorbic acid
4.5.3. Sodium bisulphite
4.5.4. Sodium EDTA
4.5.4.1. (CHELATING AGENT)
4.6. Viscosity Enhancing Agents
4.6.1. Ensures adequate measurement of volume to be dispensed and taken
4.6.2. Methylcellulose