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2/03/2003 Anna Paola Colomb

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link between the API propertieslink between the API properties

andandtheir application in formulationtheir application in formulation

PHARMACEUTICALPHARMACEUTICAL

PREPRE -- FORMULATION:FORMULATION:

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SUMMARY

Pre - formulation: definition, objective and position

Typical characterizations at pre - formulation step

from literature

from Archemis experience

Impact of drug properties on formulation: examples

Study case 1: salt screening

Study case 2: pre - formulation for a parenteral

form

Conclusion

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PrePre -- formulation:formulation:

definition and objectivedefinition and objective

First learning on chemical and physicalproperties of a drug substance

Formulation of a stable, effectiveand safe dosage form

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4/282/03/2003 Anna Paola Colomb

entre PartenairPrePre -- formulationformulation

inin pharmapharma developmentdevelopment

Toxicity

Clinic

Phase 1 Phase 3

Human

Administration

Phase 2

2 years1 years 3 years

250 molecules 5 3.5

Tolerance(max dose)healthy

volunteers

Activity(dosageform)

limited numberof patients

EfficacySafety

large scale ofpatients

Registration

1.2

Pre-clinic Commerc

ial

3-4 years

1Drugdiscovery

cha

racter

izatio

n

Form

ch

oic

e

g

kgg

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Classical troubles inClassical troubles in

prepre -- formulation studiesformulation studies

Lack of information

Little quantities

Time limitation

High wager

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The pre - formulation approach

Chemical process group

yield

purity

crystallization feasibility

cost

Formulation group

solubility

stability

processability

Drug metabolism group

toxicologic

pharmacokinetic

Team work

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Typical characterization at

pre - formulation steprom literature*:

Bulk Characterization: crystallinity, polymorphism, hygroscopicity,

ulk density, powder flow properties

. Solubility Analysis: ionization constant (pKa), pH solubility profile,

artition coefficient, dissolution.

I. Stability Analysis: stability in toxicological formulations,lution stability, solid state stability, bulk stability,compatibility

Outline of the principal areas of pre formulation research

iese and Hagen, 1986.

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Typical characterization at

pre - formulation step

Appearance, color, odor, particle size,Appearance, color, odor, particle size,crystal habit, purity, solubility, pKa,crystal habit, purity, solubility, pKa,

thermal behavior, hygroscopicity,thermal behavior, hygroscopicity,salt form availability, polymorphism, stability...salt form availability, polymorphism, stability...

From Archemis experience: from batch to batch

34

34.5

35

35.5

36

36.5

37

37.5

38

0 500 1000 1500 2000 2500

Time/mins

Masse/mg

35.4589mg

-3.15%

+6.03%

+0.16%

AA

BB

0

10

0

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180frequency q3*(x) / %

0.2 0.4 0.6 0.8 1 4 6 8 10 0 40 60 80 100 00 400

Taille de particule / m

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The preThe pre --formulation tools at Archemisformulation tools at Archemis

PropertyProperty

Particle size: Laser granulometry, sieve fractionation,

microscopy

Particle shape: Microscopy (optic, SEM)

Particle porosity: Hg porosimetryPurity: High Performance Liquid Chromatograph

Molar ratio: Nuclear Magnetic Resonance, ionic

chromatography

Crystallinity: X-Ray DiffractionHygroscopicity: Dynamic Vapor Sorption

Thermal behavior: DSC, TGA

+ solubility, pKa, stability...

Method of analysisMethod of analysis

P i

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Dissolution rate

Absorption rate

Agglomeration

Flowability

Color

Stability

*Dose / release

*Sedimentation/flocculation

(emulsion or suspension)

* Tablet and capsule

haracterization Property Impact on formulation

Impact of drug properties on formulationexamples

Particle size

t P t i

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Impact on formulation


DissolutionBioavailability

* Dose

* Release form

* Salt formation

* Complexation

* Cosolvent system...

Solubility

haracterization Property

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Impact on formulation


Shelf life

(time,

temperature,

light)

* Process(e.g. mixing, compaction,

spray drying,lyophilization)

* Excipients choice

(compatibility)

* Conditioning

(e.g. light protection,

temperature)

Stability

Propertyharacterization

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Study case of pre - formulation at Archemis / 1

Salt screening for a free baseSalt screening for a free base

The customer problem:

crystallinity, stability, hygroscopicity, melting point, solubility

The salt solution:

optimization of molecular form/structure for formulation and

administration by physicochemical changes:

F solubility ( bioavailability/dissolution vs prolonged action)F hygroscopicity

F melting pointstability

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Solvents andacids selection

Acceptablesolubility

Newselection

no yes

Salt generation

Crystallinesolid

yes no

PartiallyCrystalline

solid

noyes

RejectedCrystallizationimprovement

noyes

Further analysis:- thermal behavior- hygroscopicity- molar ratio

- purity...

Saltselection

Free base

characterization

str

ate

gy

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Free base characterization

Fingerprint of free base for salt comparison:

2 pKa determination2 RX pattern

2 Purity2Melting point2 Other thermal behavior

2 Hygroscopicity

2 Stability2 Solubility

2Microscope observation2.

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Newselection

no yes

Salt generation

Crystallinesolid

yes no


solid

noyes


noyes


- purity...

Saltselection

Free base

characterization

str

ate

gy

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Solvent and acid

selectionSolvent selection criteria:

2 ICH* class 3 preferred2 ICH* class 2 accepted

2 proticity and polarity properties

2 low boiling pointAcid:

2 pKa of counterion must be at least 2 units below that of drug2 counterions must have completed chronic toxicological tests

2 counterions must be pharmacologically inert

CH: International Conference on Harmonization: class 1 = cause unacceptable toxicit

class 2 = less severe toxicity

class 3 = less toxic solvents

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e t e a te a



Newselection

no yes

Salt generation

Crystallinesolid

yes no


solid

noyes


noyes


- purity...

Saltselection

Free base

characterization

str

ate

gy

entre PartenairSalt evaluation

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Salt evaluation

Saltpr

e-selection

by

cho

sencriteria

Free baseLot .

Salt form 1 Salt form 2

Process Crystallization in xsolvent by cooling

Sample 1.1Cr stallization b x solventeva orationSample 1.2:Crystallization in x solventby cooling

Sample 2.1:precipitation in y solventSample 2.2:precipitation in y solvent+filtration + drying at 65C

Appearance White Brown to Yellow White to brown

Molar ratio - Sample1.1 = 1:1

Sample1.2 = 1:1

Sample 2.1: 1:1

Sample 2.2: 1:1

Purity 96.3% Sample 1.1 = 98.08 %Sample1.2 = 97.2 %

Sample 2.1: 97%Sample 2.2: 96.7%

XRD Crystalline Sample 1.1: CrystallineSample1.2: Crystalline,different from sample 1.1

Sample 2.1: crystallineSample 2.2: crystalline,identical to sample 2.1

Melting range 190C210C Sample 1.1: 194CSample1.2: 96.5C

Sample 2.1: 140C - 190CSam le 2.2: 155C - 195C

Other thermalbehavior

None None Sample 2.1:6% of loss in weight

H rosco icit1.78% w/wreversible

Sample 1.1:21.67% w/w, reversibleSample1.2:16.4 % w/w, reversible

Sample 2.1:1,77% w/w, reversibleSample 2.2:2,46% w/w reversible

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Final form selection

The best compromise between:

2 Crystallinity

2Thermal stability2 Hygroscopicity

2 Solubility2Melting point2 Purity2 Scale up consideration

2..

2 And initial customer requirement of course!

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Study case of pre formulation at ARCHEMIS / 2

Pre - formulation for a parenteral form

Objective:

find a suitable parenteral formulationfor the molecule X with a target daily

dose

Highly toxic molecule glove box

entre PartenairWater

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O/W emulsion

Submicronic suspension(nanoparticles)

NO

Solubility in oil

IV SolutionSalt formation

and solubility

Solubility in

mix of solvents

Watersolubility

YES

IV solution

Solubility in

solvents(+ surfactant)

YES

NO

YES

NO

YES

YES

NO

NO

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ate

gy

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Solubility studies

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Solubility studies

Solvent selection basing on parenteral consideration :

2 hemocompatibility

2 non toxicity

2 non irritant

2 non sensibilisant

2 pharmacologically inert

2 limited viscosity

2 water miscibility

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Solubility studies

Equilibrium solubility method:

4Stir an excess of API in the chosen solvent

(until equilibrium is achieved)

saturated solution

4 Filtration

4 HPLC analysis of dissolved API

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Other studies

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Other studies

Solution phase stability

pk determination

X ray analysis

Thermal behavior studies

Microscopy examination:

ystallography and particle size

PEG 400

Solubility at 25C and 37C = f(stirring time)

0,0

2,0

4,0

6,0

8,0

10,0

0 :0 0: 0 0 2 4 :0 0: 0 0 4 8 :0 0 :0 0 7 2 :0 0 :0 0 9 6 :0 0 :0 0 1 2 0: 0 0: 0 0 1 4 4: 0 0: 0 0

Time [h:m]

Solubility[mg/ml]

solubility at 25C

[mg/ml]

solubility at 37C

[mg/ml]

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RESULTS

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RESULTS

of pre - formulation studies

u Solubility: good results in PEG 300, PEG 400 and N, N DMA:

uAqueous solution of PEG 300 minimum target dose

u Aqueous solution of N,N DMA minimum target dose

u Solution PEG 400 + Kleptose HPB to be considered

u + other basic characterizations

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CONCLUSION

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CONCLUSION

PRE - FORMULATION:

c first characterization and dosage

form choice

c multidisciplinary science

c flexibility to the customerrequirement

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CONCLUSION

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CONCLUSION

PRE - FORMULATION

Importance of early selection

continuing the development of a non-optimal form ma

esult in:

/ inadequate and variable bioavailability

/ restrictive manufacturing conditions

/ limited shelf - life and packaging options/ increased developmental and production costs

a later change of form delays drug development

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