PHYSICOCHEMICAL ASPECTS

AND STABILITY CONSIDERATIONS WITH

LIQUID AND SEMI-SOLID LIPIDIC DOSAGE
FORMS

Elizabeth B. Vadas, Ph.D.

InSciTech Inc.

InSciTech – AAPS, March 2007 1

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 WHY DO COMPOUNDS FAIL IN
PRECLINICAL/CLINICAL DEVELOPMENT?

•LACK OF EFFICACY – 30%

•ANIMAL TOXICOLOGY – 11%
•ADVERSE EFFECTS IN HUMANS – 10%
•COMMERCIAL REASONS – 5%
•POOR “DRUG-LIKE” PROPERTIES – 39%

KENNEDY, DRUG DISCOVERY TODAY 2, (1997), 436-444

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 “DRUG-LIKE” PROPERTIES

•BIOPHARMACEUTICAL FACTORS

•STABILITY

•MANUFACTURABILITY

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 BIOPHARMACEUTICAL FACTORS
REASONS FOR POOR ORAL ABSORPTION
CHARACTERISTICS

POOR AQUEOUS SOLUBILITY

SLOW RATE OF DISSOLUTION
PERMEABILITY - EFFLUX
FIRST PASS METABOLISM

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 BIOPHARMACEUTICAL CHARACTERIZATION
•BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)

- FOUR CLASSES BASED ON COMBINATION OF AQUEOUS SOLUBILITY

AND GASTROINTESTINAL PERMEABILITY
- IMPORTANCE OF DOSE WITH RESPECT TO GI VOLUME AND GI
SOLUBILITY
- ROLE OF ABSORPTIVE TRANSPORTERS AND EFFLUX MECHANISMS
AND IMPORTANCE OF METABOLISM

BIOPHARMACEUTICS DRUG DISPOSITION CLASSIFICATION

SYSTEM (BDDCS)

Amidon et al.
Dressman et al.
Benet et al.
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 MARKETED DRUGS vs. CURRENT NCEs
IN DEVELOPMENT

MARKETED DRUGS NCEs

Class 1 ~ 35 % ~ 5%
Class 2 ~ 30 % ~ 70 %
Class 3 ~ 25 % ~ 5%
Class 4 ~ 10 % ~ 20 %

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 WHAT IS A POORLY SOLUBLE DRUG?
IMPOSSIBLE TO DEFINE WITHOUT KNOWLEDGE OF DOSE

Molecule Dose Solubility Volume needed

(mg) (mg/mL) to dissolve (mL)

Piroxicam 20 0.007 ~2,900

Digoxin 0.5 0.024 ~21

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 APPROACHES TO FORMULATE
MOLECULES THAT BELONG TO CLASS 2

•LEAD OPTIMIZATION (RARE)

•CRYSTAL MODIFICATIONS - USE OF
METASTABLE POLYMORPHS, SOLVATES, SALTS,
CO-CRYSTALS, AMORPHOUS FORM
•PARTICLE SIZE REDUCTION –MICRONIZATION,
NANOPARTICLES (BALL MILLING OR DENSE GAS
TECHNOLOGIES)

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 APPROACHES TO FORMULATE MOLECULES
THAT BELONG TO CLASS 2 – cont’d

AMORPHOUS SYSTEMS – SOLID SOLUTIONS/DISPERSIONS

drug in polymer
drug in polymer + surfactant
LIPID BASED FORMULATIONS
liquids, semi-solids, solids
drug in true solution, in a solubilized form, or in suspension
as either the crystalline or amorphous form

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 WHAT IS THE GOAL OF THE FORMULATION
APPROACH?

•ELIMINATE DISSOLUTION RATE LIMITATIONS

•PRESENT THE MOLECULE TO THE GI TRACT IN

SOLUBILIZED FORM

•MAINTAIN MOLECULE IN SOLUBILIZED FROM

IN THE GI TRACT AS LONG AS POSSIBLE

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 SOME THINGS TO CONSIDER

SOLUBILITY – thermodynamics
DISSOLUTION – kinetics
AQUEOUS vs. LIPID SOLUBILITY
THE FATE OF THE SOLUBILIZED MOLECULE
UPON INGESTION
THE FATE OF LIPID DERIVED EXCIPIENTS UPON
INGESTION

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 USE OF LIPID BASED EXCIPIENTS
IN DRUG DELIVERY
SOLUBILITY AND BIOAVAILABILITY ENHANCEMENT –
IMMEDIATE RELEASE FORMULATIONS*
IMPROVE PHARMACOKINETIC PROFILES AND/OR REDUCE
SIDE EFFECTS –MODIFIED RELEASE FORMULATIONS*
TASTEMASKING
PROTECTION FROM ENVIRONMENT – WATER SENSITIVE
MOLECULES
LUBRICATION
TOPICAL FORMULATION - BASE, SOLUBILIZER, PENETRATION
ENHANCER
* critical to consider what
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 TYPES OF FORMULATION WITH LIPIDIC
EXCIPIENTS-ORAL DRUG DELIVERY
SIMPLE SOLUTIONS OR SUSPENSIONS IN EDIBLE OILS
SOLUTIONS IN MIXTURES OF EXCIPIENTS
SEDDS – self-emulsifying drug delivery systems
S-SEDDS – supersaturable self-emulsifying dds
SMEDDS – self-emulsifying microemulsion dds
PRESENTATION: SOFT AND HARD GELATIN CAPSULES,
GRANULAR SOLIDS

C.W.POUTON, EUR.J.PHARM.SCI. 2006, 29, 278-287

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 ARE LIPID BASED EXCIPIENTS VERSATILE?

MULTIPLE CHOICES WITHIN EXCIPIENT CLASS

MULTIPLE FORMULATION OPTIONS
MULTIPLE PROCESSING OPTION
SUITABLE FOR MOISTURE SENSITIVE MOLECULES
LOW COST
SAFETY
ENVIRONMENTALLY FRIENDLY

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 TYPES OF EXCIPIENTS FOR LIPID BASED
FORMULATIONS

LIQUIDS
ABSORPTION ENHANCERS
propylene glycol monocaprylate
macrogol glycerides
glyceryl monooleate

VEHICLES
medium chain triglycerides

SOLVENTS
diethylene glycol monoethyl ether
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 TYPES OF EXCIPIENTS FOR LIPID BASED
FORMULATIONS – cont’d

SEMI-SOLIDS
BIOAVAILABILITY ENHANCERS
lauroyl and stearoyl macrogol glycerides
TASTE MASKING AGENTS
glyceryl palmitostearate
MODIFIED RELEASE AGENTS
glyceryl behenate, glyceryl palmitostearate
LUBRICANTS
glyceryl behenate, glyceryl palmitostearate
VEHICLES
glycerol esters of fatty acids

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 SELECTION OF THE APPROPRIATE
FORMULATION APPROACH

CRITICAL TO DEFINE THE GOAL OF THE FORMULATION

CRITICAL TO UNDERSTAND THE CHEMISTRY OF THE
EXCIPIENTS
CRITICAL TO UNDERSTAND THE SOLID STATE PROPERTIES
AND THERMAL BEHAVIOR OF THE LIPIDIC EXCIPIENTS

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 WHAT ARE “LIPIDIC” EXCIPIENTS?

OILS and FATS – fatty acids linked to glycerol by

ester bonds
WAXES – fatty acids linked to long chain alcohols
by ester bonds
SIMPLE PHOSPHOLIPIDS
COMPLEX PHOSPHOLIPIDS AND DERIVATIVES

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 VERSATILITY AND COMPLEXITY
•EXCIPIENTS DERIVED FROM LIPIDS CAN BE LIQUID,
SEMISOLID OR SOLID AT ROOM TEMPERATURE
•WIDE RANGE OF FATTY ACID CHAIN LENGTHS AND
VARYING AMOUNTS OF UNSATURATED BONDS
•AQUEOUS SOLUBILITY VARIES WITH FATTY ACID
CHAIN LENGTH
C2 – C6 soluble in water
C8 – C10 partially soluble in water
C>12 insoluble in water

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 HOW SIMPLE IS SIMPLE?
CORN OIL – C8, 10, 12, 14, 16, 18 saturated
C18:1
C18:2
SUNFLOWER OIL – C16, 18 saturated
C18:1
C18:2
C18:3
LONGER CHAIN LENGTH -Tm INCREASES
HIGHER NUMBER OF UNSATURATED BONDS- Tm DECREASES

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 UNDERSTANDING THE CHEMISTRY

FATS AND OILS – FATTY ACIDS LINKED TO GLYCEROL BY

ESTER BONDS – MONO, DI AND TRIGLYCERIDES
EXAMPLE: GELUCIRE 44/14
•PREPARED BY THE ESTERIFICATION OF HYDROGENATED
PALM KERNEL OIL AND PEG 1500
•SEMISOLID AT RT, Tm = 44 C0 , HLB = 14
•DEFINED MIXTURE OF MONO, DI AND TRIGLYCERIDES,
MONO AND DIESTERS OF PEG AND FREE PEG
•FATTY ACID COMPOSITION : C8 TO C18

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 EXCIPIENT STABILITY CONSIDERATIONS

SOME FATTY ACIDS ESTERIFIED WITH ALCOHOLS MAYBE

SENSITIVE TO OXYDATION OR HYDROLYSIS
•OXYDATION OF UNSARURATED BONDS IN THE FATTY
ACID CHAINS
•OXYDATION OF LONG CHAIN ALCOHOLS AT ELEVATED T
•HYDROLYSIS OF THE ESTER BOND

ALL OF THE ABOVE CAN BE CONTROLLED

DURING FORMULATION AND STORAGE

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 COMPLEX SOLID STATE BEHAVIOUR
•LIPIDS EXHIBIT POLYMORPHISM

•DIFFERENT CRYSTALLINE PHASES CAN COEXIST

•TRANSITIONS AMONG PHASES CAN OCCUR UPON

HEAT TREATMENT

•RATE OF COOLING WILL AFFECT RATE OF

CRYSTALLIZATION; SLOW vs RAPID CRYSTALLIZATION
WILL RESULT IN DIFFERENT SPATIAL ARRANGEMENTS

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 COMPLEX SOLID STATE BEHAVIOR, cont’d
THE EXCIPIENTS MAYBE SUPERCOOLED – EFFECT ON
NUCLEATION AND CRYSTAL GROWTH
RAPID COOLING IS NOT DESIRABLE SINCE IT MAY RESULT IN
FORMULATIONS THAT WILL CHANGE UPON STORAGE
EFFECT OF DRUG MOLECULE ON THE BEHAVIOR OF LIPIDIC
CARRIERS – soluble, insoluble
DORDUNOO et al., J. Pharm. Pharmacol. 1996, 48 782-789

DSC STUDY OF SOLIDIFICATION BEHAVIOR AT DIFFERENT

COOLING RATES OF PEG1500, PEG2000, PEG4000, PEG6000
AND GELUCIRE 44/14

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 SOME OF THE TECHNIQUES USED IN THE
CHARACTERIZATION OF LIPID BASED
FORMULATIONS
THERMAL ANALYTICAL METHODS; DSC, TGA, HOT
STAGE MICROSCOPY
XRPD
PHASE SOLUBILITY
PARTICLE SIZE ANALYSIS
DISSOLUTION
IN VITRO LIPOLYSIS

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 DEVELOPMENT TOOLS VS ASSESSMENT
OF STABILITY

DEVELOMENT: chemical assay, thermal analytical methods,

solubility measurements, phase diagrams,
non-compendial dissolution, XRPD, in vitro lipolysis

SELECTION OF APPROPRIATE ICH STORAGE CONDITIONS FOR

STABILITY ASSESSMENT

STABILITY PROGRAM: stability indicating assay, thermal

analytical methods, XRPD, compendial dissolution

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 SOME OF THE ISSUES
IN LIPID BASED DRUG DELIVERY
COMPLEX SOLID STATE BEHAVIOR (real)
INSUFFICIENT KNOWLEDGE OF THE EXCIPIENTS AND LACK
OF UNDERSTANDING OF THE FATE OF THE LIPID BASED
FORMULATION IN THE GI TRACT (real)
LONG TERM PHYSYCAL and CHEMICAL STABILITY (not
specific/unique to lipid based formulations)
BATCH TO BATCH VARIABILITY (perceived)
TOO MANY CHOICES (perceived)
COMPLEXITY OF SOME OF THE FORMULATIONS (both
perceived and real)
FRAGMENTED LITERATURE (real)
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 Conference

www.conference.is/m3

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