Unit 2: Solubilizing Excipients in Pharmaceutical Formulations

Introduction:
1. Many drugs have poor water solubility and poor dissolution rate. Hence a solubilizing agent
should be used in formulations to improve solubility and dissolution rate of drugs.
2. pH modifiers, organic solvents, and surfactants are widely used as solubilizing agents.
Oral Formulations:
1. Oral formulations include, tablets, capsules, soft gelatin capsules, solutions, syrups, and elixirs.
2. Solubilizing excipients are used for good oral bioavailability and quick onset of action.
3. Micellar solubilization, complexation, solid dispersion and solvent deposition techniques are
used to develop oral products.
4. Table 1 shows some examples of commercially available solubilized oral formulations.
5. Table 2 shows some examples of solubilizing excipients in oral dosage forms.
Table I
Commercial Product Excipients
1. Progesterone soft gelatin capsule Peanut oil
2. Nimodipine soft gelatin capsule Peg 400, peppermint oil, water
3. Phenobarbital elixir Ethanol
4. Digoxin soft gelatin capsule Ethanol, PEG 400, propylene glycol
Table II: Solubilizing Excipients Used in Commercial Formulations
Water Soluble Water Insoluble Surfactants
Ethanol Glyceryl mono oleate Cremophor EL
Glycerol Glycerol esters of fatty acids (Gelucires) Tween 20, Tween 80
PEG 300 Propylene glycol esters of fatty acids Span 20
PEG 400 Medium chain mono glycerides PEG 300 caprylic glycerides
Poloxamer 407 Medium chain di glycerides Gelucires
Propylene glycol Medium chain tri glycerides PEG 400 mono sterates
Hydroxy propyl β Castor oil, corn oil, cotton seed oil, soy PEG 1750 mono sterates
cyclo dextrin bean oil, olive oil, peanut oil, sesame
oil, hydrogenated vegetable oils
Oleic acid, Soy fatty acids, Tocopherols
Water Soluble Organic Solvents:
1. PEG 400, ethanol, propylene glycol, glycerol, transcutol HP are used for solubilization.
2. Advil soft gel caps have ibuprofen solubilized in PEG 400 and medium chain triglycerides.
3. Nimotop soft gel capsules have 30 mg nimodipine solubilized in mixture of peppermint oil and
PEG 400.
Surfactants in Oral Formulations:
1. Water miscible surfactants have a hydrophilic portion and lipophillic portion. They solubilize
drugs in their micelle structure.
2. Cremophors, tweens, spans, gelucires, PEG 400 mono sterates are used in commercial
formulations.
3. Targretin soft gelatin capsules has bexarotene (anti cancer drug) solubilized in a mixture of
tween 20 and PEG 400.
Water Insoluble Organic Solvents:
1. The water insoluble solvents used in commercial formulations are oleic acid, tocopherol (vitamin
E), long chain / medium chain / short chain triglycerides, peanut oil, castor oil, corn oil, cotton
seed oil, soya bean oil, olive oil, and sesame oil.
2. Example: Prometrium soft gelatin capsules have 100 mg progesterone solubilized in peanut oil.
3. Example: Valproic acid (anti convulsant) is solubilized in corn oil.
Water Insoluble Solids:
1. They include hydrogenated vegetable oils and hydrogenated soya bean oils.
2. They are used to solubilize lipophillic drugs.
3. Vesanoid soft gel caps have tretinoin, an anti cancer drug. It is sollubilized in soya bean oil.
Micro emulsion Oral Formulations:
1. Microemulsions are stable, clear dispersions having a polar solvent, oil, a surfactant and a
cosurfactant.
2. Microemulsions have very good potential for delivery of hydrophobic molecules.
3. All the commercial products are SEDDS (self emulsifying drug delivery systems). Upon contact
with gastro intestinal fluids, they form a fine micro emulsion.
4. Fenofibrate is a lipid lowering drug and is solubilized in a mixture of gelucire 44/14, PEG
20000, and hydroxyl propyl cellulose and is filled into hard gelatin capsules (Fenogal). On oral
administration, it forms a micro emulsion in GIT and drug is readily absorbed.
Injectable Formulations:
1. These include IV bolus, IV infusion, IM bolus, sub cutaneous and implants (osmotic pumps).
2. Solubilization techniques for injectable formulations are same as that for oral formulations. pH
adjustment, co solvency, cyclo dextrin complexation, emulsions, liposomes, and combination of
these techniques.
3. The below table gives different solubilizing excipients used in injections.

Solubilizing Excipients Used in Commercial Injectable Formulations

Water Soluble: Ethanol, Glycerol, Propylene glycol, N – methyl – 2 - pyrrolidine , PEG 300, PEG
400, Poloxamer 407, Hydroxy propyl β cyclo dextrin, Di methyl acetamide,
Di methyl sulfoxide, Sulfo butyl ether β cyclo dextrin, Phospho lipids.
Water Insoluble: Castor oil, Sesame oil, Cotton seed oil, Safflower oil, Soy bean oil, Soy fatty
acids, Medium chain tri glycerides.
Surfactants: Cremophor EL, Tween 20, Tween 80, Solutol

4. The below table gives some examples of commercial formulations in market.

Commercial Injectable Formulations

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 Commercial Product
1. Digoxin injection, 0.25 mg/ml, i.m.
2. Itraconazole, 10 mg/ml
3. Pentobarbital sodium, 50 mg/ml, i.m.
4. Propofol, emulsion , IV, 10 mg/ml
Excipients
Propylene glycol 40 %, ethanol 10 %
Hydroxy propyl β cyclo dextrin 40 %, propylene
glycol 2.5 %
Propylene glycol 40 %, ethanol 10 %
Soybean oil 100 mg/ml, glycerol 22.5 mg/ml, egg
lecithin 12 mg/ml,

Water Soluble Organic Solvents in Injections:

1. The water soluble organic solvents used in commercial injectable formulations are given in the
table.
2. Alcohol and propylene glycol are widely used co solvents in injectable formulations.
3. PEG 300 and PEG 400 are safest organic solvents.
4. N – methyl – pyrrolidine (NMP) is a very strong solubilizing agent.
Surfactants in Injections:
1. Tween 80 is a surfactant commonly used to solubilize drug molecules in injections.
2. Taxotere has docetaxel (anti cancer) 40 mg/ml in 100 % tween 80, which is diluted with saline
before I.V infusion.
3. Solutol HS is non ionic solubilizer and is used up to 7 % to solubilize vitamin K.
Cyclodextrins in Injections:
1. Sulfo butyl ether β cyclo dextrin (Captisol) ia very safe and stable water soluble excipients.
2. It forms inclusion complexes and is an excellent solubilizer.
3. Itriconazole is solubilized by 40 % hydroxyl propyl beta cyclo dextrin and is administered by IV
injection after dilution.

Phospholipids for Injections:

1. Phospholipids are used to make liposomes which can solubilize the drug.
2. Liposomes are tiny vesicles (bubble) made of phospho lipid molecules. They can be filled with
drugs and used for drug targeting.
3. Phospholipid molecules self-assemble into spherically bi layer membranes. The polar heads are
hydrated with water, and the hydrophobic chains interact with each other as shown in the below
figure. The thickness of the lipid bilayer of the liposomes is around 5 nm.
4. Phospholipids used to prepare liposomes are phosphatidyl cholines (PC), phosphatidyl
ethanolamines (PE), and phosphatidyl glycerols (PG).

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 5. The inner core is aqueous and the area
between the tails is lipophillic and can give
accommodation for lipophillic drug
molecules.
6. Ambisome is a sterile freeze dried
liposomal product, having 50 mg of
amphotericin B. It is reconstituted before IV
use.
Emulsions as Injections:
1. Oil soluble molecules can be formulated for IV injection by making an o/w emulsion.
2. A typical emulsion contains 20 % soybean oil , 2 % glycerol, 1 % egg lecithin and pH between 7
to 8 and is injected by IV bolus or infusion.
3. Total parenteral nutrition (TPN) formulations are emulsions administered by IV infusion as
nutritional supplements.
Oily Injectable Formulations:

1. Vegetable oils can be used to prepare oily solutions of lipophillic drugs.

2. They are given intra muscularly. The form a drug depot in the muscle and the drug releases for
two to four weeks.

3. The oils used in commercial injections include castor oil, cotton seed oil, sesame oil, soy bean oil
and safflower oil.

4. Example: Haloperidol deaconate is dissolved in sesame oil and is given by I.M route.

5. Example: Testosterone enanthate is dissolved in sesame oil and is given by I.M every two weeks.
Transdermal Formulations:

1. Transdermal formulations delevier the drug through the skin. Example: Topical ointments,

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 creams, solutions and patches which are placed over the skin.
2. Solublizing solvents for transdermal formulations are DMSO, ethanol, NMP, PG, dipropylene
glycol, span 80, transcutol HP, mineral oil, oleic acid, oleyl alcohol, lecithin and triacetin.
3. Example: Transdermal Scop patches are widely used by travelers for motion sickness. It contains
1.5 mg of scopolamine solubilized in mineral oil. It delivers 1 mg over a period of 3 days.
4. Topical solutions are applied topically to the skin on areas of treatment. Example: Herpid
contains antiviral drug idoxuridine solubilized in DMSO and is used in treatment of Herpes
rashes.

Connclusions:
1. Existing solubilizing excipients can solubilize most of the drugs. However, new excipients and
techniques are to be developed on a continuous basis to solubilize new drugs.
2. It is generally difficult, costly and time consuming (years) to establish a new excipient as safe for
formulation.

Dr. Eswar Gupta Maddi, M.Pharm., Ph.D.,

Professor and Head, Dept. of Pharmaceutics, Sir C.R. Reddy College of Pharmaceutical Sciences,
Eluru, West Godavari district, A.P, India 534007. Cell: +91 988 55 237 60,
email: meguptas@yahoo.com, meguptas@gmail,com