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MSc. Jorge Mendonça Líder e coordenador projeto FACT BRASIL Far-Manguinhos / FIOCRUZ 17de Abril de 2008

MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

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Page 1: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

MSc. Jorge Mendonça

Líder e coordenador projeto FACTBRASIL

Far-Manguinhos / FIOCRUZ17de Abril de 2008

Page 2: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Rede FACTDNDi/TDR:

coordenaçãocientífica e gestão de

projeto

Uni Bordeaux, France:desenvolvimento

farmacêutico de AS/AQ

Uni Sains, Malaysia:devt of metodologia

analítica, PK humanos & animal

Uni Oxford, UK: PK/PD, estudos in vitro and

moleculares

Uni Mahidol, Thailand:

ensaio clínico deAS/MQ

Far Manguinhos, Brazil:desenvolvimento

farmacêutico de AS/MQ, toxicologia

CNRFP, Burkina Faso:

ensaio clínico de AS/AQ

Modelo colaborativo da DNDi ilustrado pelo Projeto FACT

AS/AQ: artesunato/amodiaquinaAS/MQ: artesunato/mefloquinaPK/PD: farmacocinética/farmacodinâmica

-- - - - - Informação compartilhada----------- Informação/dados/métodos compartilhados

DNDi, MSF, TDR, Far-Manguinhos, EC’s INCODEV: financiamento

Um Projeto Global

Page 3: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

• América do Sul;• Ásia;• Possivelmente África.

Um produto Global

ASMQO comprimido azul dos trópicos

Page 4: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

MISSÃO:Contribuir para a promoção da saúde pública, por meio da produção de medicamentos, do desenvolvimento tecnológico e difusão de conhecimentos.

VISÃO: Ser um centro de referência da pesquisa, do desenvolvimento e da produção farmacêutica brasileira.

FOCO: Priorizar o acesso da população brasileira aos programas governamentais de saúde.

FARMANGUINHOS

Page 5: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

ÁÁREAS ENVOLVIDAS NO PROJETO FACTREAS ENVOLVIDAS NO PROJETO FACT

PMAPMA

ENGENHARIA ENGENHARIA

PCPPCP

CQCQ

AARAAR

COMERCIALCOMERCIAL

Ministério da SaúdeMinistério da Saúde

PRODUÇÃOPRODUÇÃO Controle da Qualidade

Controle da Qualidade

NVQNVQ GQGQ

LTF LDVA

Page 6: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Qualidade LDVA /NVQÉrico Daemon

Tecnologia Farmacêutica LTFAlessandra Viçosa

Consultores do projeto (CATALENT, Dra Isabela Ribeiro eDra. Luciana Barros)

Coordenador local – Jorge Mendonça

Estrutural Organizacional FACT - Farmanguinhos

Page 7: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Jorge Mendonça

Far-Manguinhos / FIOCRUZ17de Abril de 2008

Page 8: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

ASMQ ASMQ

The development of a coThe development of a co--formulationformulation

Page 9: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

FROM THE FROM THE BLUEBLUEPRINT TO THE PRINT TO THE BLUE BLUE PILL PILL

BLUEBLUEPRINTPRINT BLUE BLUE PILLPILL??

9

Page 10: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

BLUEBLUEPRINTPRINT

THE THE BLUEBLUEPRINT OF THE PRINT OF THE BLUE BLUE PILL PILL

•• Quality components (AS, MQ, Excipients)Quality components (AS, MQ, Excipients) �� ���� ��

•• Smallest possible size (Minimum excipients)Smallest possible size (Minimum excipients) �� ���� ��

•• Good aspect (Coating)Good aspect (Coating) �� ���� ��

•• Paediatric strengthsPaediatric strengths

•• Simple (1 or 2 tables for 3 days)Simple (1 or 2 tables for 3 days) �� ���� ��

•• Stable (Process and Tropical conditions)Stable (Process and Tropical conditions) �� ���� ��

•• Adequate biopharmaceutical properties.Adequate biopharmaceutical properties.

10

Page 11: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

APIs Characteristics ?APIs Characteristics ?

MEFLOQUINE HYDROCHLORIDEMEFLOQUINE HYDROCHLORIDE ARTESUNATEARTESUNATE

XX

Stability: Not Critical issueStability: Not Critical issue Stability: Critical issueStability: Critical issue

11

Page 12: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Mefloquine HydrochlorideMefloquine Hydrochloride

Manufacturer: Abbott GmBH & Co. KG Manufacturer: Abbott GmBH & Co. KG -- Germany/ Sifavitor Germany/ Sifavitor –– Italy (Italy (New supplierNew supplier)) ��

EE--DMF available, Comply with EPDMF available, Comply with EP

Exists in known different polymorphs (A,B,C,D and E)Exists in known different polymorphs (A,B,C,D and E) ��

Other Preformulation tests:Other Preformulation tests:

Bulk and Tapped densityBulk and Tapped densityHausner ratio: FairHausner ratio: Fair �� ���� ��Carr index: FairCarr index: Fair �� ���� ��Repose angle: Repose angle: PoorPoor ��Water content: MWater content: Mááx 3 %x 3 %Particle size distributionParticle size distributionThermal analysisThermal analysisX X –– rayray

Problem: Poor Flow !Problem: Poor Flow !

12

Page 13: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

ArtesunateArtesunate

Manufacturer: Knoll AG Manufacturer: Knoll AG -- SwitzerlandSwitzerland

EE--DMF available, FDA inspected Manufacturing Site, Comply with IP.DMF available, FDA inspected Manufacturing Site, Comply with IP.

Artesunate does not show polymorphism.Artesunate does not show polymorphism.

Particle size profile (Knoll)Particle size profile (Knoll) ��

Batches 2.05 4.05Batches 2.05 4.05

Different Particle size profile !!!Different Particle size profile !!!dd

5050= 77= 77µµmm dd

5050= 132= 132µµmm

13

Page 14: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Formulation designFormulation design

Simple compositionSimple composition

Artesunate Artesunate -- APIAPI

Mefloquine Hydrochloride Mefloquine Hydrochloride -- APIAPI

Microcrystalline cellulose Microcrystalline cellulose -- DiluentDiluent

Sodium croscarmellose Sodium croscarmellose -- DisintegrantDisintegrant

Magnesium stearate Magnesium stearate –– LubricantLubricant

Opadry white Opadry white -- CoatingCoating

Blue Lake FDC 2 Blue Lake FDC 2 -- CoatingCoating

APIs APIs -- About 70 % of the formulationAbout 70 % of the formulation

Excipients Excipients -- About 30 % of the formulationAbout 30 % of the formulation

Simple compositionSimple composition

Artesunate Artesunate -- APIAPI

Mefloquine Hydrochloride Mefloquine Hydrochloride -- APIAPI

Microcrystalline cellulose Microcrystalline cellulose -- DiluentDiluent

Sodium croscarmellose Sodium croscarmellose -- DisintegrantDisintegrant

Magnesium stearate Magnesium stearate –– LubricantLubricant

Opadry white Opadry white -- CoatingCoating

Blue Lake FDC 2 Blue Lake FDC 2 -- CoatingCoating

Simple compositionSimple composition

Artesunate Artesunate -- APIAPI

Mefloquine Hydrochloride Mefloquine Hydrochloride -- APIAPI

Microcrystalline cellulose Microcrystalline cellulose -- DiluentDiluent

Sodium croscarmellose Sodium croscarmellose -- DisintegrantDisintegrant

Magnesium stearate Magnesium stearate –– LubricantLubricant

Opadry white Opadry white -- CoatingCoating

Blue Lake FDC 2 Blue Lake FDC 2 -- CoatingCoating

Coating function: Taste masking , light protection and good aspect

Stable formulation: APIs x Stable formulation: APIs x ExcipientsExcipients compatibilitycompatibility

Smallest excipient quantitiesSmallest excipient quantities Smallest tablet sizeSmallest tablet size

14

Page 15: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

High dosage X Low dosageHigh dosage X Low dosage

High DosageArtesunate + Mefloquine (100 +220)

mg

Low DosageArtesunate + Mefloquine (25 +55) mg

Average mass/4 = Average mass/4 =

Same formulation and different average massSame formulation and different average mass

No problems to child administration in the

spoon !!

Fast disintegration time

15

Page 16: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

And about the quality of excipients?And about the quality of excipients?

Microcrystalline cellulose Microcrystalline cellulose –– Comply with EP Comply with EP

Sodium croscarmellose Sodium croscarmellose -- Comply with EPComply with EP

Magnesium stearate Magnesium stearate –– Comply with EP Comply with EP -- Animal originAnimal origin

�� Very important to good processability in production area.Very important to good processability in production area.

Opadry whiteOpadry white

Blue Lake FDC 2Blue Lake FDC 2Pharmaceutical gradePharmaceutical grade

The nice aspect of the The nice aspect of the BLUE BLUE tablets required tablets required

this kind of materials.this kind of materials.

16

Page 17: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Process Choice/ Optimizing StabilityProcess Choice/ Optimizing Stability

Tabletting

Mixing

Mefloquine Dry Granulation

Coating

Packaging

To improve MQ flowTo improve MQ flow

Addition of Artesunate Addition of Artesunate –– DryDry processprocess

Aluminium foilAluminium foil

High Humidity ProtectionHigh Humidity Protection Clinical Trial packagingClinical Trial packaging

17

Page 18: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Dosing ScheduleDosing Schedule

18

Page 19: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Packaging (Simplicity and Patient Compliance)Packaging (Simplicity and Patient Compliance) �� ���� ��

6 to 11 months 6 – 11 years1 – 5 years 12 years or older

19

Page 20: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

DR profiles of tabletsDR profiles of tablets

MQ releaseMQ release

AS releaseAS release

20

Page 21: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Stability / Liability of the product : stress testingStability / Liability of the product : stress testing

MQ

UNK 2

DHA 1

UNK 1

Table 11. Qualitative comparision of chromatograms in solid state stress conditions Sample/Condition Control Sample

(non degraded) Heat (Chamber) Humidity Light

Artesunate

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

4

.80

1

070

53

6

Detector A (211nm)FACTMPAScontrole1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

arte

suna

to

4.65

12

2292

1

Detector A (211nm)FACTuMPASaquec1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

4

.51

107

43

75

Detector A (211nm)FACTMPAScontroleumid1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

arte

sun

ato

4.

28

12

138

90

Detector A (211nm)FACTrMPAScontroleluz2

NameRetention TimeArea

Mefloquine

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

Mef

loqu

ina

18.

32

22

0675

326

Detector A (211nm)FACTMPMQcontrole1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

(Art

es

una

to)

1

2.2

4 1

895

6

me

flo

quin

a

16

.88

20

70

823

79

Detector A (211nm)FACTMPMQaquec1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

1

3.3

7

32

30

6

1

8.5

2

23

339

38

82

Detector A (211nm)FACTMPMQumid1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

me

flo

quin

a

17.

77

2

31

92

349

8

Detector A (211nm)FACTMPMQluz1

NameRetention TimeArea

Drug Product (pulverized)

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

arte

sun

ato

4.

86

993

530

mef

loq

uina

18

.57

19

6539

129

Detector A (211nm)FACTcompPApulvcontrole1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

Art

es

una

to

4.3

7

663

29

1

8

.79

6

915

8

1

2.1

0 9

18

52

Me

floq

uin

a 1

6.8

3 1

44

992

502

1: 211 nm, 8 nmFACTcomprimidospulvaquec1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

Art

esu

nato

4

.58

10

928

46

9

.22

17

399

1

2.4

8

381

38

mef

loqu

ina

1

8.7

1 2

279

514

63

Detector A (211nm)FACTcomprimidospulvumid1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

Art

esun

ato

4.1

7 6

077

07

8

.59

615

7

1

1.0

0

226

02

Me

floqu

ina

17.

86

158

3085

32

1: 211 nm, 8 nmFACTcomprimidospulvluz1

NameRetention TimeArea

Placebo

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15Detector A (211nm)FACTExcipienteumid1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15Detector A (211nm)FACTExcipienteaquec2

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15Detector A (211nm)FACTExcipienteumid1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15Detector A (211nm)FACTExcipienteluz1

NameRetention TimeArea

Drug Product (5 tablets) a

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

arte

sun

ato

4.

86

993

530

mef

loq

uina

18

.57

19

6539

129

Detector A (211nm)FACTcompPApulvcontrole1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

Art

esu

nato

4.

37

6836

38

8

.80

19

669

1

2.13

55

948

Mef

loqu

ina

16

.80

1

4735

770

2

1: 211 nm, 8 nmFACT5comprimidosaquec1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mA

U

-5

0

5

10

15

Art

esu

nat

o 4

.58

10

887

33

9

.22

22

695

1

2.4

2 2

353

3

me

floqu

ina

18

.65

22

5093

583

Detector A (211nm)FACT5comprimidosumid1

NameRetention TimeArea

Minutes

0 5 10 15 20 25 30 35 40 45

mAU

-5

0

5

10

15

Art

es

una

to

4.1

7 6

836

06

8

.50

90

78

1

0.8

3

273

31

Me

floq

uin

a 1

7.8

1

155

464

440

1: 211 nm, 8 nmFACT5comprimidosluz1

NameRetention TimeArea

a= non pulverized, intacts

•~3% of unknown impurities in oxidative conditions •Strong degradation with heat•Excipients not found to increase degradation

•Stability-indicating assay and related substances method•Degradation peaks from artesunate• <1 % degradation to light and humidity

HPLC-3D detector

21

Page 22: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Stability Studies Stability Studies –– 36 Months36 Months

22

Page 23: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

The Product: 1st Fixed-Dose ACT with 3-Year Shelf Life

23

Page 24: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Manufacturing History and StatusManufacturing History and Status

Batches Size 2x 100 Kg4 x 16 Kg

Batches Size Batches Size 2x 100 Kg2x 100 Kg4 x 16 Kg4 x 16 Kg

Stability StudiesStability Studies

Drugs used in:Drugs used in:-- Thailand StudiesThailand Studies-- Acre/ParAcre/Paráá Clinical TrialsClinical Trials

20042004

Acre/ParAcre/ParááClinical TrialsClinical Trials

Batches Size 2x 16 Kg

Batches Size Batches Size 2x 16 Kg2x 16 Kg

Batches Size 2x 16 Kg

Batches Size Batches Size 2x 16 Kg2x 16 Kg

April 2

008 !

20062006

Batches Size 2x 12 Kg

Batches Size Batches Size 2x 12 Kg2x 12 Kg

20072007 Jan/ 2008Jan/ 2008

ValidationBatches

ValidationValidationBatchesBatches

Acre Clinical TrialsAcre Clinical TrialsNew MQ Supplier BatchesNew MQ Supplier Batches

Market BatchesMarket Batches

24

Page 25: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

THE THE BLUE BLUE PILL PILL

�� Quality components (AS, MQ, Excipients)Quality components (AS, MQ, Excipients) �� ���� ��

�� Smallest possible size (Minimum excipients)Smallest possible size (Minimum excipients) �� ���� ��

�� Good aspect (Coating)Good aspect (Coating) �� ���� ��

�� Paediatric strengthsPaediatric strengths

�� Simple (1 or 2 tables for 3 days)Simple (1 or 2 tables for 3 days) �� ���� ��

�� Stable (Process and Tropical conditions)Stable (Process and Tropical conditions) �� ���� ��

�� Adequate biopharmaceutical properties.Adequate biopharmaceutical properties.

25

Page 26: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Jorge Mendonça

Far-Manguinhos / FIOCRUZ17de Abril de 2008

Page 27: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

• Facilidade de Uso (1 ou 2 cps por dia);• Uso pediátrico;• Menor tamanho possível e bom aspecto;•Estável tanto em processo quanto emcondições tropicais;• Mais barato que os medicamentos isolados.

Conceitos do projeto

Page 28: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

PROCESSOS E PESSOAS

Page 29: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

TIME FACT

Page 30: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

TIME ANALÍTICO

Page 31: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Estudo clínico na Tailândia

Page 32: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Estudo clínico no Acre

Page 33: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Produção

Page 34: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Produção

Page 35: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

Agradecimentos:

• Farmanguinhos FIOCRUZ• DNDi• Dr. Jean-René Kiechel• Dra. Isabela Ribeiro• Eloan Pinheiro• Eduardo Costa• Dra. Núbia Boechat

Page 36: MSc. Jorge Mendonça · Artesunate does not show polymorphism. Particle size profile (Knoll) Batches 2.05 4.05 Different Particle size profile !!! d 50 = 77 µm d 50 = 132 µm 13

OBRIGADO PELA ATENÇÃO

[email protected] (Coordenador)[email protected] (Tecnologia Farmacêutica)[email protected] (Qualidade)[email protected] (consultora)