1. Excipients in solution dosage forms Pharm D, PhD of Pharmaceutics
Dr. Zahra Hesari
Pharm D, PhD of Pharmaceutics
Guilan University of Medical Sciences, Faculty of Pharmacy

2. Solubility affecting factors
Polymorphism
High Solubility
High Stability
Particle size
Micronized powder pH
Weak base (75%) pH Solubility
Weak acid (20%) pH Solubility
atropine, codeine

3. Solubility affecting factors
Complex formation
Glycin, Xanthan gum, NaCMC
Solubilizing agents
Co-solvent
Surfactant
Critical micelle concentration (CMC)
Anionic
Cationic
Nonionic
Amphoteric

4. Critical micelle concentration (CMC)

5. Solubility affecting factors
Solid dispersion
Surfactant
PEG, Sugars
Cyclodextrins (α,β,γ,etc)

6. General Water Solubility Trends (Minerals)
1. All compounds of the ammonium ion (NH4+), and of the Alkali metal (Group IA) cations, are soluble. 2. All nitrates and actetates are soluble. 3. All chlorides, bromides, and iodides are soluble EXCEPT those of silver, lead, and mercury(I). 4. All sulfates are soluble EXCEPT those of silver, lead, mercury(I), barium, strontium, and calcium. 5. All carbonates, sulfites, and phosphates are insoluble EXCEPT those of ammonium and Alkali metal (Group IA) cations. 6. All hydroxides are insoluble EXCEPT those of ammonium, barium, and alkali metal (Group IA) cations. 7. All sulfides are insoluble EXCEPT those of ammonium, Alkali metal (Group I) cations, and Alkali earth metal (Group II) cations. 8. All oxides are insoluble EXCEPT those of calcium, barium, and Alkali metal (Group I) cations; these soluble ones actually react with the water to form hydroxides.

7. Negative Ions (Anions) + Positive Ions (Cations) =
Solubility of Compounds in water
Example
any anion
Alkali Ions
(Li+, Na+, K+, Rb+, Cs+, Fr+)
soluble
Sodium fluoride, NaF, is soluble
hydrogen ion
[H+ (aq)]
hydrogen chloride, HCl, is soluble
ammonium ion
(NH4)
ammonium chloride, NH4Cl, is soluble
nitrate
NO3-
any cation
potassium nitrate, KNO3, is soluble
acetate
(CH3COO-)
(except Ag)
sodium acetate, CH3COONa, is soluble
Chloride (Cl-),
Bromide (Br-), Iodide (I-)
Ag+, Pb2+, Hg2+, Cu+, Tl+
low solubility (insoluble)
silver chloride, AgCl, forms a white precipitate
any other cation
potassium bromide, KBr, is soluble
Sulfate
(SO42-)
Ca2+, Sr2+, Ba2+, Ag2+, Pb2+, Ra2+, Hg2+
barium sulfate, BaSO4, forms a white precipitate
copper sulfate, CuSO4, is soluble
sulfide
(S2-)
alkali ions (Li+, Na+, K+, Rb+, Cs+, Fr+),
alkali earth metals (Be2+, Mg2+, Ca2+, Sr2+, Ba2+, Ra2+),
and H+(aq), and NH4+
magnesium sulfide, MgS, is soluble
zinc sulfide, ZnS, is insoluble

8. alkali ions (Li+, Na+, K+, Rb+, Cs+, Fr+), Sr2+, Ba2+, Ra2+, Tl+,
hydroxide
OH- +
alkali ions (Li+, Na+, K+, Rb+, Cs+, Fr+),
Sr2+, Ba2+, Ra2+, Tl+,
and H+(aq), and NH4 =
soluble
strontium hydroxide, Sr(OH)2, is soluble
any other cation
low solubility (insoluble)
silver hydroxide, AgOH, is insoluble (forms a precipitate)
Phosphate (PO43-),
Carbonate (CO32-),
Sulfite (SO32-)
ammonium phosphate, (NH4)3PO4, is soluble
magnesium carbonate, MgCO3, is insoluble
Chromate
CrO42-
Ca2+, Sr2+, and NH4+,
sodium chromate, Na2CrO4, is soluble

9. General Water Solubility Trends (organic compounds)
1-5 carbons (linear) with –COOH, -OH,… groups are soluble
Increase in carbon number results in decrease in solubility (linear molecules)
Cyclic structures decrease the solubility
Branches in carbonic chain increases the solubility
Hydrophilic groups increase the compound solubility

10. Ideal solvent Affordable Non-toxic Compatible No pharmacologic effect
Viscosity
High dissolving
Taste, color, odor
Drug characteristics and application

11. Types of solvents
Industrial solvents (manufacture synthesis and extraction)
methanol, ethanol, propyl alcohol, glycols, chloroform, acetone,…
Oral solutions (limited)
Water, ethanol, glycerin, PG, PEG (300 or 400)
Topical solutions
Isopropyl alcohol, benzyl alcohol, PEG, ethyl isopropyl, palmitic&myristic acid butyl esters (Isopropyl myristate& butyl palmitate)
Injectable solutions
Water for injection, ethyl oleate, almond oil, sesame oil, olive oil (rare), benzyl alcohol, PG

12. Common solvents & Co-Solvents
Water
Advantage and disadvantages
In compounding formulas
Distilled water
Fresh boiled & cooled purified water
Removal of CO2 & O2
WFI
Purified Water, USP
Distillation
Ion exchange treatment
Reverse osmosis
fewer solid impurities
Preparation of aqueous dosage forms except injections
United States Pharmacopoeia,
‘Bacteriostactic Water for Injection’.

13. Ethanol (Ethyl alcohol)
Primary solvent for organics
Water miscibility
Hydroalcoholic mixture
Co-solvent (formulation, synthesis,
extraction)
Oral & topical (not in injections)
Preservative (20%)
Co-surfactant
Skin preparations
Pharmacologic and potential toxic Effects
USP ethanol: % in 15.56°C
Alcohol ethylic/industrial: pure
Absolute/ dehydrated alcohol: 99.5% pathology examinations, research
FDA recommendation for OTC oral drug products:
under 6 years of age: 0.5%
6 to 12 years of age: 5%
over 12 years of age: 10%

14. Isopropyl Rubbing Alcohol
Diluted Alcohol, NF
equal volumes of Alcohol, USP, and Purified Water, USP
final volume
strength of Diluted Alcohol
useful hydroalcoholic solvent in pharmaceutical processes and preparations
Rubbing Alcohol
70% ethyl alcohol by volume
Remainder: water, denaturants, color additives, perfume oils, and stabilizers.
Denaturants: 8 parts of acetone, 1.5 parts of methyl isobutyl ketone
Bitter substances: sucrose octaacetate (355mg) or denatonium benzoate (1.4mg)
volatile and flammable
soothing rub for bedridden patients, a germicide for instruments,
and a skin cleanser prior to injection.
Isopropyl Rubbing Alcohol
70% by volume isopropyl alcohol
Remainder: water, color additives, stabilizers, and perfume oils
Rubefacient and soothing rub and as a vehicle for topical products
Commercially available 91% isopropyl alcohol
Diabetic patients: needles & skin

15. Oral solvents (dissolving power)
Glycerin (Glycerol)
Triol
Co-solvent
Surfactant
Preservative
Sweetener
Stabilizer
Humectant (Hygroscopic)
Propylene Glycol (PG)
Taste & viscosity
Poly Ethylene Glycol (PEG)
Oral solvents (dissolving power)
Water < glycerin < PEG&PG < alcohol
Sorbitol
sweetener & viscosity modifying

16. Preservatives Water, sweetener (sucrose), multiuse
Contamination resources:
Raw materials (water, sugar), containers, mixers, manufacturing machines, pipelines, filling machines, operators, storehouse, ventilation, consumer
Ideal preservative
Broad spectrum
Stable (physical, chemical, microbiologic)
Good solubility
Non toxic, non allergic, no pharmacologic effect, no taste & odor
Effective
Affordable

17. Preservative classification
Acidic preservatives
Phenols
Para hydroxy benzoic acid’s alkyl esters (Parabens)
Methyl Paraben (anti bacterial)
Propyl Paraben (antifungal)
Benzoic acid & Na Benzoate
Boric acid & Na Borate
Sorbic acid & Na/K sorbate
K sorbate (antifungal)
2. Neutral preservatives
Alcohols, benzyl alcohol, phenyl ethyl alcohol,
chlorobutanol

18. Preservative classification
3. Mercury compounds
Thimerosal, phenyl mercuric acetate, nitromerosal,
phenyl mercuric nitrate
4. Ammonium quaternary compounds
cetylpyridinium chloride, Benzalkonium chloride
Bitter taste
Methyl paraben 0.18% + Propyl paraben 0.02%