SPECIAL LIPIDS

INTRODUCTION

40-50% of NCEs- sparingly soluble compounds that require specialized formulations.

This is where the role of lipid excipients comes in play - used as co-solvents or as carriers to protect the API and improve its p’cokinetic and p’codynamic activity.

Lipids are hydrocarbon based molecules. Thus they are predominantly hydrophobic, but also have a hydrophilic functional portion, such as hydroxyl, amine, phosphate esters and carboxyl groups.

This makes lipids- a group of amphipathic molecules that posses both hydrophobic and hydrophilic portions to self assemble into various colloid structures in physiological conditions.

Fatty acids Natural oils and fats Semi-synthetic mono-, di-, triglycerides Semi-synthetic PEG derivatives of glycerides

and fatty acids Polyglyceryl fatty acid esters Phospholipids Cholesterol Glycolipids

Classification

Fatty Acids

A Fatty acid is a carboxylic acid with a long unbranched aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28.

Saturated Fatty acids

Stearic acid, an 18-carbon saturated fatty acid

Unsaturated fatty acid

Fatty acids having one or more double-bonds between carbon atoms.

Oleic acid, an 18-carbon monounsaturated fatty acid

STEARIC ACID

Functional Category -Emulsifying agent; solubilizing agent; tablet and capsule lubricant

Applications in Pharmaceutical Formulation or Technology – in oral formulations as a tablet and capsule lubricant; as a binder or in combination with shellac as a tablet coating. It has also been suggested that stearic acid may be used in enteric tablet

coatings and as a sustained-release drug carrier In topical formulations, stearic acid is used as an emulsifying and solubilizing

agent. When partially neutralized with alkalis or triethanolamine, stearic acid is used in

the preparation of creams. Incompatibilities- Stearic acid is incompatible with most metal

hydroxides and may be incompatible with bases, reducing agents, and oxidizing agents.

Ointment bases made with stearic acid may show evidence of drying out or lumpiness due to such a reaction when compounded with zinc or calcium salts. Stearic acid has been reported to cause pitting in the film coating of tablets applied using an aqueous film-coating technique; the pitting was found to be a function of the melting point of the stearic acid

SEMI-SYNTHETIC MONO-,DI- & TRIGLYCERIDES

These excipients are compatible with both soft and hard gelatin capsules.

-Used as solubilizing vehicles,emulsifiers,suspending agents,wetting agents and in various controlled release dosage forms.

-Fatty acid content and composition of semi-synthetic glycerides are more uniform than natural glycerides but certain amount of variability can be expected.

-Variability is a funtion of excipient brand as well as particular manufacturing lot of a given excipient.

SEMISYNTHETIC PEG DERIVATIVESPolyethylene glycol (PEG) is a polyether compound.PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular weight.Structural formula and molecular weight of typical polyethylene glycol polymer. GRADE AVERAGE MOLECULAR WEIGHT

PEG200 190-210

PEG300 285-315

PEG400 380-420

PEG600 570-613

PEG900 855-900

Applications

Parenterals

ophthalmic

Used in biodegradable

polymeric matrices used in controlled-

release systems

Topical

Aqueous polyethylene

glycol solutions can be used either

as suspending agents or to adjust the

viscosity and consistency of

other suspending vehicles.

As Suppository Bases

Polyoxyethylene Stearates The polyoxyethylene stearates are a series of polyethoxylated

derivatives of stearic acid. Functional Category:-

Name and molecular weight:-

Emulsifying agent

Solubilizing agent

Wetting agent

NAME MOLECULAR WEIGHT

Polyoxyl 6 stearate 548.80

Polyoxyl 8 stearate 636.91

Polyoxyl 12 stearate 813.12

Polyoxyl 20 stearate 1165.55

Polyoxyl 40 stearate 2046.61

Polyoxyl 50 stearate 2487.15

Polyoxyl 100 stearate 4689.80

COMMERCIAL PRODUCT

COMPOUND COMMERCIAL PRODUCT

PEG-4-distearate Kessco®200 DS (Stepan)

PEG-6-distearate Kessco®PEG 300 DS (Stepan)

PEG-12-distearate Kessco®PEG 600 DS (Stepan)

PEG-8 Stearate Cithrol™ 4MS

PEG-8 Isostearate Cithrol™ 4MIS

Croda’s group of polyethylene glycols and polyol esters are now to be known under the below tradenames. Polyethylene glycols and polyol esters offer diverse properties for the formulation of a wide range of consumer care and industrial systems.

Old Trade name Chemical Description New Trade name

CITHROL™ 10MO PEG-20 Oleate Cithrol™ 10MO

CITHROL™ 10MS (VEG)

PEG-20 Stearate Cithrol™ 10MS

ESTOL™ 3751 PEG-6 Beeswax Cithrol™ 3BW

ARLACEL™ P135 LAN

PEG 30 Dipolyhydroxystearate

Cithrol™ DPHS

Polyoxyethylene alkyl ethers are nonionic surfactants.

Polyoxyethylene Alkyl Ethers

Functional Category

DescriptionThey are colorless, white, cream-colored or pale yellow materials with a slight odor. They vary considerably in their physicalappearance from liquids, to pastes, to solid waxy substances based on m.w.

Emulsifying agentPenetration enhancer

Solubilizing agent Wetting agent

Commercially available grades

Name Physical form

HLB Value

Application

CREMOPHOR A25

MICROBEADS

15-17 Used as emulsifier for o/w emulsion, creams.

VOLPO S2 White translucentplastic wax

4.9 Used in microemulsion gels, creams and lotions, physical sunscreens, lipsticks, aqueous/alcoholic preparations, depilatories, antiperspirants and deodorants and shaving preparations.

Polyoxyethylene alkyl ethers are prepared by the condensation oflinear fatty alcohols with ethylene oxide. The reaction is controlled so that the required ether is formed with the polyethylene glycol of the desired molecular weight.

Method of Manufacture

New applications:Polyoxyethylene alkyl ethers have been studied in drug delivery systems containing oleosomes, hydrosomes, phosphosomes, vesicles and niosomes.

It is found to have an enhanced skin permeation of drugs such as ibuprofen and clotrimazole.

Enhanced ocular absorption of insulin from eye drops, and an ocular insert device have been observed using polyoxyethylene alkyl ethers in the formulation systems.

It shows effective enhancement in the intestinal absorption of poorly absorbed hydrophilic compounds.

Synonym : Glycerine fatty acid ester

Composition : chain of glycerol molecules ( linked together by ether linkage) + esterified fatty acid molecules (1-2)

Eg – polyglyceryl -6 dioleate is a chain of 6 glycerol molecules esterified with 2 molecules of oleic acid .

General structure :

POLYGLYCERYL FATTY ACID ESTERS

HLB : Hydrophilicity with in poly glycerol chain length and no. of free OH groups , and with no. or chain length of esterified fatty acid.

Therefore , the hydrophilicity can range from low , approaching that of triglycerides(polyglyceryl-6 octastearate , HLB 2.5 ) to high (polyglyceryl-10 mono,dioleate , HLB 11 .)

Ranges from : liquid – waxy saturated – unsaturated water soluble - oil soluble compounds .

Non toxic

Biodegradable : degrades to glycerol and fatty acid in the body .

Applications : surfactant , solubilizers , vehicles ,emulsifiers and drug crystallization inhibitor in pharmaceuticals .

Other applications : emulsifier and stabilizer in food industries , cosmetics – soap , shampoo etc .

PHOSPHOLIPIDS • Amphiphilic molecules • Formed by phosphate grp linkage to the terminal –OH grp of

glycerols• COMMON HEAD Grps: choline(Phosphatidylcholine),

ethanolamine (Phosphatidylethanolamine),serine(Phosphatidylserine), etc.

• Because of their amphiphilic nature, phospholipids will associate at hydrophobic/hydrophilic interfaces

Functional Category- Anionic, cationic, nonionic surfactant biodegradable material; dispersing agent; emulsifying agent; emulsion stabilizer; solubilizing agent;

Applications in Pharmaceutical Formulations-• stabilize emulsions and suspensions• In formulations administered as lung surfactants, in intravenous fat

emulsions, and in oral solutions (e.g. Rapamune)• To form various types of liposomes eg.1. Unilamellar 2. Multilamellar3. Multivescicular

Examples

Common name

Trade name manufacturer synonym

Dilauroyl phosphatidylcholine

Coatsome MC-2020PhosphoLipid-DLAPC

NOFNippon DLPC

Dimyristoyl phosphatidylcholine

Coatsome MC-4040Lipoid PC 14:0/14:0 (DMPC) PhosphoLipid-DMPC

NOFLipoid Nippon DMPC

CHOLESTEROL

• Nonproprietary NamesBP: CholesterolJP: CholesterolPhEur: CholesterolUSP-NF: Cholesterol• SynonymsCholesterin; cholesterolum.• Chemical Name and CAS Registry NumberCholest-5-en-3b-ol [57-88-5]• Empirical Formula and Molecular WeightC27H46O 386.67• Structural Formula

• Functional CategoryEmollient; emulsifying agent.

• Applications in Pharmaceutical Formulation or Technology

1. Cholesterol is used in cosmetics and topical pharmaceutical

formulations at concentrations of 0.3–5.0% w/w as an emulsifying agent.

2. It imparts water-absorbing power to an ointment and has emollient activity.

3. Cholesterol also has a physiological role. It is the major sterol of the higher animals, and it is found in all body tissues, especially in the brain and spinal cord.

• Incompatibilities -Cholesterol is precipitated by digitonin

• Related Substances -Lanolin; lanolin alcohols; lanolin hydrous.

REFERENCES

Handbook of pharmaceutical excipient Oral lipid-based formulations Avanti polar

lipids(www.avantilipids.com)