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Presented By : Rupsa S. Ghosh M.Pharm Semester-IV Guided by: Prof. S. B. Bumrela HOD, Pharmaceutics Sinhgad Institute of Pharmaceutical Sciences, Lonavala (Pune) Department of Pharmaceutics

M.PHARM_ Rupsa Ghosh

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Presented By :

Rupsa S. Ghosh

M.Pharm Semester-IV

Guided by:

Prof. S. B. Bumrela

HOD, Pharmaceutics

Sinhgad Institute of Pharmaceutical Sciences, Lonavala (Pune)

Department of Pharmaceutics

13 March 20152

₪ Introduction

₪ Literature Review

₪ Aims and Objectives

₪ Plan of work

₪ Materials and Methods

₪ Drug Profile

₪ Result and Discussion

₪ Summary and Conclusion

₪ References

CONTENTS

INTRODUCTION

13 March 2015

3

Aqueous solubility is one of the key determinants in development of new

chemical entities as successful drugs.

Formulation of poorly soluble compounds face typical problems viz a too low

oral bioavailability and erratic absorption due to their very low saturation

solubility and dissolution rate.

The conventional methods used for improvement of solubility and dissolution

rate fails to increase the bioavailability.

13 March 2015

4

CO-CRYSTALS

Co-crystal is a crystalline structure consisting of two or more components that

form a unique structure having specific properties. They are also known as

“solid crystals , multi-molecular complexes, molecular compounds, organic

molecular compounds, addition compounds, and solid state complexes”.

13 March 2015

5

A pharmaceutical co-crystal is a single crystalline solid that incorporates two

neutral molecules, one being an active pharmaceutical ingredient (API) and the

other a co-crystal former.

The components in a co-crystal exist in a definite stoichiometric ratio

(1:1;1:2;1:1.5), and assemble via non-covalent interactions such as hydrogen

bonds, ionic bonds, π-π or Vander Waals interactions rather than by ion

pairing.

13 March 2015

6

CO-FORMERS

13 March 2015

7

Co-crystal former may be an excipient or another drug.

It should have at least one functional group from amine, amide, aldehyde,

ketone, thio ketone, ether, pyridine, imidazole, indole, pyrrolidine, carboxyl,

carbonyl, phenol, sulfone, sulfonyl, mercapto and methyl thio.

Examples: Mallic Acid, Nicotinamide, Benzoic Acid.

Saccharin Urea

DRUG SELECTION CRITERIA

13 March 2015

8

The ability of an API to form co-crystal depends on

Type of co-former

API: co-former ratio

Solvent

Temperature

Pressure

Crystallization technique

13 March 20159

Advantages of Co-crystals

All types of molecules can form co-crystals

No

by products formed

An opportunity to address

Intellectual Property (IR)

issues

High

yield

techniques

LITRETURE REVIEW

13 March 2015

10

13 March 2015

11

Sr.

No.

Title Detail Of Work How Useful Ref.

No.

1 Performance

comparison of a

Co-Crystal of

Carbamazepine

with marketed

product

Physical and chemical stability of the co-

crystal is similar to the pure drug in the

marketed product (Tegretol) & oral BA in

dogs shows the co-crystal to be a viable

alternative to the anhydrous polymorph in

formulated solid oral products.

Evaluation parameters

of resultant co-

crystals. 2

2 Co-Crystals of

Efavirenz with

selected Co-

formers:

preparation and

characterization

Co-crystals were prepared using solvent drop

grinding and solvo-thermal method.

Equilibrium solubility profile of EFA-Oxalic

acid dihydrate (1:1) & EFA-Citric acid

monohydrate (1:1) shows an enhancement of

1.8 &2.7 folds of solubility of Efavirenz as

compared to commercial sample.

Method of preparation,

determination of

stoichiometric ratio of

co-formers.

3

13 March 201512

3 Improving the

Solubility of

Agomelatine via

Co-crystals

Four co-crystals of Agomelatine with urea

Glycolic acid, Isonicotinamide , & Methyl4-

hydroxybenzoate in 1:1 stoichiometry were

synthesized via six kinds of synthons. The

solubility of Agomelatine is much improved in

PB pH 6.8& are approx.2.2, 2.9, 4.7, &3.5

times greater than that of Agomelatine Form II,

& 1.6, 2.1, 3.4&2.5 times than that of Form I.

Selection of

co-formers.

6

4 Characterization

of Prulifloxacin-

Salicylic Acid

Complex by

IR,DSC And

PXRD

Co-crystals of Prulifloxacin-Salicylic acid were

prepared in different molar conc. by kneading

method using mortar and pestle for 30mins

&characterized using IR,DSC, PXRD. The

resultant co-crystals showed improved

solubility and in turn dissolution rate than the

pure drug.

Time of

grinding,

solubility

and

dissolution

studies

7

Sr.

No.

Title Detail Of Work How Useful Ref.

No.

13 March 2015

13

AIMS AND OBJECTIVES

13 March 201514

To investigate different methods of preparation for co-crystals.

To prepare co-crystals by solvent drop grinding and solvent evaporation

methods.

To evaluate the physicochemical properties of prepared co-crystals.

a) Particle morphology

b) Crystalline state evaluation

- Powder X-ray Diffraction (PXRD)

- Differential Scanning Calorimetry (DSC)

c) Solubility determination of the co-crystals.

d) Formulation and optimization of co-crystals into tablet dosage form.

e) In- vitro drug dissolution study and comparison with marketed product.

f) Stability study of the optimized formulation.

PLAN OF WORK

13 March 2015

15

13 March 201516

1.Selection of poorly soluble drugs.

2.Selection of co-crystal formers.

3.Methods of preparation: Different techniques for the preparation of co-crystals

are present. However, in the present work these following methods are used

a) Solvent drop grinding technique

b) Solvent evaporation technique

4.Physiochemical characterization of:

Drugs and co-crystal formers.

Prepared co-crystals.

In- vitro dissolution studies of prepared co-crystals.

Formulation of co-crystals into tablets.

13 March 201517

5. Drug-Excipient compatibility study by FT-IR.

6. Evaluation studies of the tablet formulations .

7. Comparison of in-vitro dissolution of co-crystal formulations with marketed

products of the same drugs.

8. Optimization of the tablet formulation using 22 full factorial designs and

statistical analysis of the data.

9. Stability study of the optimized formulation as per ICH guidelines.

MATERIALS AND METHODS

13 March 2015

18

List of chemicals and their manufacturers

13 March 2015

19

Sr. No. Materials Manufacturers

1. Atorvastatin Calcium Dr. Reddy’s Lab, Hyderabad

2. Saccharine InsolubleShree Vardayini Chemical Industries Pvt.

Ltd., Gujarat

3. UreaDNS Fine Chemicals and Laboratories (P)

Ltd, Mumbai

4. Croscarmellose sodium A.B. Enterprises, Mumbai

5. Microcrystalline Cellulose A.B. Enterprises, Mumbai

6. Hydroxypropyl Cellulose A.B. Enterprises, Mumbai

7. Lactose Monohydrate Shreenath Chemicals, Mumbai

8. Calcium Carbonate Oasis Fine Chemicals, Gujarat

9. Magnesium Stearate Shreenath Chemicals, Mumbai

DRUG PROFILE

13 March 2015

20

13 March 2015

21

STRUCTURE

CAS NO. 134523-00-5

IUPAC NAME (βR,8R)-2-(4-

fluorophenyl)-α,δ-dihydroxy-5-(1-

methylethyl)-3-phenyl-4-

[(phenylamino)carbonyl]-1H-pyrrole-1-

heptanoic acid trihydrate.

MOLECULAR FORMULA C66H68CaF2N4O10

MOLECULAR WEIGHT 1155.36

MELTING POINT 176-177 ºC

DESCRIPTION A white to off-white, crystalline powder.

SOLUBILITY Highly soluble in methanol

CATEGORY HMG-CoA Reductase Inhibitors

ATORVASTATIN CALCIUM

RESULTS AND DISCUSSION

13 March 2015

22

13 March 201523

Pre-formulation studies of Atorvastatin Calcium

1. Melting Point - 176-178 ºC

2. Solubility

3. Determination of λmax

Sr. No. Solution Inference

1. Distilled water Very slightly soluble

2. Phosphate buffer pH 6.8 Very slightly soluble

3. Ethanol (95%) Slightly soluble

4. Methanol Freely soluble

Fig1- UV spectra of Atorvastatin Calcium in methanol

13 March 201524

Sr. No. Conc.(µg) Absorbance

1 5 0.1328

2 10 0.267

3 15 0.4969

4 20 0.5033

5 25 0.6091

4. Calibration curve of Atorvastatin Calcium in Methanol

Fig2- Calibration curve of ATC in methanol

13 March 201525

5. Differential Scanning Calorimetry(DSC)

6. Powder X-ray diffraction (PXRD)

Fig3-DSC curve of ATC

Fig4-PXRD curve of ATC

13 March 201526

Pre-formulation studies of co-crystals

Sr. No. Parameters Observation

1 Organoleptic properties

Colour White (ATC: SAC)

Off- white(ATC:UREA)

Odour Odorless

2 Melting point

ATC +Sac ( solvent grinding)

ATC +Sac ( solvent evaporation)

187-190ºC

192-194ºC

ATC +Urea ( solvent grinding)

ATC +Urea (( solvent evaporation)

164-168ºC

168-170ºC

3 Solubility studies

Distilled water More than pure drug

Methanol Highly soluble

13 March 201527

Fig5- Microscopic PhotographsA) ATC: SAC co-crystal by SE B) ATC: SAC co-crystal by SG

C) ATC: UREA co-crystal by SE D) ATC: UREA co-crystal by SG

13 March 201528

Fig6- FTIR spectra of pure Atorvastatin Calcium

Peak Inference

NH =3500-3100cm-1 Stretching

OH =3650-3200cm-1 Stretching

C=O =1536cm-1 Amide

Fourier Transform Infrared Spectroscopy (FTIR)

13 March 201529

A Pure Urea

B Co-crystal (SE)

C Co-crystal (SG)

A)

B) C)

Fig 7- FTIR spectra of

13 March 201530

Sr. No. IR Spectrum Peak (cm-1) Groups Inference

1. Atorvastatin

Calcium

3510.77 N-H Stretching

--1459.85 N-H Bending

1676.8 C=O Amide

3580.2 O-H Stretching

2.

Urea 1691.27 C=O Ketone

--3505.95 N-H Stretching

3600.3 O-H Free

3.

ATC: UREA co-

crystal (SE)

3510.77 N-H Stretching Confirms

formation of inter-

molecular H- bond

1459.85 N-H Bending

3442.31 O-H Bonded

4.

ATC: UREA co-

crystal (SG)

3510.77 N-H Stretching Confirms

formation of inter-

molecular H- bond

1459.85 N-H Bending

3444.24 O-H Bonded

FT-IR interpretation of Atorvastatin Calcium: UREA co-crystals

13 March 201531

A Pure saccharine

B Co-crystal(SG)

C Co-crystal(SE)

Fig8- FTIR spectra ofA)

B) C)

13 March 201532

Sr. No. IR Spectrum Peak (cm-1) Groups Inference

1. Atorvastatin

Calcium

3510.77 N-H Stretching

--1580.38 N-H Bending

1676.8 C=O Amide

3580.2 O-H Stretching

2.

Saccharin 1723.09 C=O Ketone

--3613.95 O-H Stretching

1055 O=S=O

Sulfones

1337.39 C-N

3.

ATC: SAC

co-crystal (SE)

1728.44 C=O Ketone Confirms

formation of inter-

molecular H- bond3666.36 O-H Stretching

4. ATC: SAC

co-crystal (SG)

1728.36 C=O Ketone Confirms

formation of inter-

molecular H- bond3706.06 O-H Stretching

FT-IR interpretation of Atorvastatin Calcium: Saccharin co-crystals

13 March 201533

Drug- excipient compatibility

Fig 9- FT-IR spectra of

Physical mixture of ATC:

SAC co-crystal and excipients

a) ATC : SAC co-crystal +

Calcium carbonate

b) ATC: SAC co-crystal +

Croscarmellose Sodium

c) ATC: SAC co-crystal +

Microcrystalline Cellulose

d) ATC: SAC co-crystal+

Hydroxypropyl Cellulose

e) ATC: SAC co-crystal+

Lactose Monohydrate

f ) ATC: SAC co-crystal+

Magnesium stearate

13 March 201534

Fig 10- FT-IR spectra of Physical

mixture of ATC: UREA co-

crystal and excipients

a) ATC: UREA co-crystal+

Calcium carbonate

b) ATC: UREA co-crystal+

Croscarmellose Sodium

c) ATC: UREA co-crystal+

Microcrystalline Cellulose

d) ATC: UREA co-crystal+

Hydroxypropyl Cellulose

e) ATC: UREA co-crystal+

Lactose Monohydrate

f) ATC: UREA co-crystal+

Magnesium stearate

13 March 201535

Characterization of co-crystals

1. . Differential Scanning Calorimetry(DSC)

Fig11- DSC curves of

a) Pure ATC

b) ATC: SAC co-crystal (SE)

c) ATC: SAC co-crystal (SG)

d) ATC: Urea co-crystal (SE)

e) ATC: Urea co-crystal (SG)

13 March 201536

2. Powder X-ray diffraction (PXRD)

Fig12- Powder X-ray

diffraction patterns of ATC

and Co-crystals.

13 March 201537

1 Media 900ml of PB pH 6.8

2 Time 30mins

3 Apparatus USP-II

4 Speed 75rpm

3. In-vitro dissolution of co-crystals

Fig13 - Comparative dissolution profiles of drug and ATC: SAC co-crystals

13 March 201538

1 Media 900ml of PB pH 6.8

2 Time 30mins

3 Apparatus USP-II

4 Speed 75rpm

Fig14- Comparative dissolution profiles of drug and ATC: UREA co-crystals

13 March 201539

Formulation design of Atorvastatin Calcium co-crystal tablets

1. Preparation of tablet granules by wet granulation technique

Weighed quantity of Co-crystal+ half quantity of CCS+ HPC+

Lactose monohydrate all passed through sieve 40

Granulation with distilled water & drying at 55ºC in Hot air oven for

2hrs.

Prepared granules are shifted through sieve30 &mixing of rest

amount of CCS for 10mins

Addition of Magnesium sterate & mixing for 5mins

Granules ready for compression

13 March 201540

Optimization of tablet formulation by 22 full factorial designs

Factors used:

The amount of Croscarmellose Sodium (X1)

Hydroxypropyl Cellulose (X2)

Levels used:

High level (+1)

Low level (-1)

Responses measured:

Drug release (Y1)

Hardness (Y2)

13 March 201541

Sr. No. Ingredients

(mg/tablet)

F1 F2 F3 F4

1. ATC: Sac co-

crystal(SE)

20 20 20 20

2. Croscarmellose

Sodium

3 6 3 6

3. Microcrystalline

Cellulose

50 50 50 50

4. Hydroxypropyl

Cellulose

4 10 10 4

5. Lactose

Monohydrate

120 111 120 111

6. Calcium

Carbonate

1 1 1 1

7. Magnesium

Stearate

2 2 2 2

Formulation design for Atorvastatin Calcium: Saccharine co-crystal

(Solvent evaporation technique) tablets

13 March 201542

Sr. No. Ingredients

(mg/tablet)

F5 F6 F7 F8

1. ATC: Urea co-

crystal(SE)

20 20 20 20

2. Croscarmellose

Sodium

3 6 3 6

3. Microcrystalline

Cellulose

50 50 50 50

4. Hydroxypropyl

Cellulose

4 10 10 4

5. Lactose

Monohydrate

120 111 120 111

6. Calcium

Carbonate

1 1 1 1

7. Magnesium

Stearate

2 2 2 2

Formulation design for Atorvastatin Calcium: Urea co-crystal

(Solvent evaporation technique) co-crystal tablets

13 March 201543

Sr. No. Ingredients

(mg/tablet)

F9 F10 F11 F12

1. ATC: Sac co-

crystal(SG)

20 20 20 20

2. Croscarmellose

Sodium

3 6 3 6

3. Microcrystalline

Cellulose

50 50 50 50

4. Hydroxypropyl

Cellulose

4 10 10 4

5. Lactose

Monohydrate

120 111 120 111

6. Calcium

Carbonate

1 1 1 1

7. Magnesium

Stearate

2 2 2 2

Formulation design for Atorvastatin Calcium: Saccharine co-crystal

(Solid grinding technique) co-crystal tablets

13 March 201544

Sr. No. Ingredients

(mg/tablet)

F13 F14 F15 F16

1. ATC: Sac co-

crystal(SG)

20 20 20 20

2. Croscarmellose

Sodium

3 6 3 6

3. Microcrystalline

Cellulose

50 50 50 50

4. Hydroxypropyl

Cellulose

4 10 10 4

5. Lactose

Monohydrate

120 111 120 111

6. Calcium

Carbonate

1 1 1 1

7. Magnesium

Stearate

2 2 2 2

Formulation design for Atorvastatin Calcium: Urea co-crystal

(Solid grinding technique) co-crystal tablets

13 March 201545

Contour Plots

Fig-15 -Contour Plot of factorial variables on

Hardness. The shaded region indicates the

range of response variable Hardness (Y2)

Fig16 - Contour Plot of factorial variables on

Drug Release. The shaded region indicates the

range of response variable, Drug Release (Y1)

13 March 201546

Response-surface analysis

Fig17- Response surface plot of factorial

variables (CCS & HPC) on Hardness. The

shaded region indicates the range of response

variable, Hardness (Y2)

Fig18 - Response surface plot of factorial

variables (CCS & HPC) on Drug Release. The

shaded region indicates the range of response

variable, Drug Release (Y1)

13 March 201547

Statistical Analysis using ANOVA

Response 2 Hardness

ANOVA for selected factorial model

Analysis of variance table [Partial sum of squares - Type

III]

Sum of

squares

d

f

Mea

n

Squa

re

F

Valu

e

p-

valu

e

Pro

b >

FSource

Model 2.002225 1

2.00

2225

59.5

4572

0.01

64

signif

icant

B-Hydroxy

Propryl

Cellulose 2.002225 1

2.00

2225

59.5

4572

0.01

64

Residual 0.06725 2

0.03

3625

Cor Total 2.069475 3

Response 1 Drug Release

ANOVA for selected factorial model

Analysis of variance table [Partial sum of squares - Type

III]

Sum

of

Squa

res df

Mea

n

Squa

re

F

Valu

e

p-

valu

e

Pro

b >

FSource

Model

45.0

0085 2

22.5

0043

241.

875

0.04

54

signi

fican

t

B-Hydroxy

Propryl

Cellulose

38.8

7523 1

38.8

7523

417.

9008

0.03

11

AB

6.12

5625 1

6.12

5625

65.8

4923

0.07

81

Residual

0.09

3025 1

0.09

3025

Cor Total

45.0

9388 3

13 March 201548

Evaluation of precompression parameters

Sr. No. Parameters F1 F2 F3 F4

1 Bulk

density(g/ml)

0.465 0.482 0.477 0.496

2 Tapped

density(g/ml)

0.570 0.595 0.582 0.611

3 Hausner’s ratio 1.23 1.23 1.22 1.23

4 Compressibility

index

19.29 18.99 18.04 18.82

5 Angle of

repose(º)

28.81 31.46 29.24 30.52

Pre compression parameters of ATC: SAC co-crystal (SE) granules

13 March 201549

Sr. No. Parameters F5 F6 F7 F8

1 Bulk

density(g/ml)

0.505 0.512 0.515 0.523

2 Tapped

density(g/ml)

0.610 0.630 0.612 0.621

3 Hausner’s ratio 1.22 1.11 1.18 1.18

4 Compressibility

index

18.03 16.33 15.84 15.78

5 Angle of

repose(º)

30.96 33.02 31.38 29.68

Pre compression parameters of ATC: UREA co-crystal (SE) granules

13 March 201550

Sr. No. Parameters F9 F10 F11 F12

1 Bulk

density(g/ml)

0.536 0.559 0.521 0.547

2 Tapped

density(g/ml)

0.620 0.644 0.620 0.632

3 Hausner’s ratio 1.16 1.09 1.19 1.16

4 Compressibility

index

14.51 13.19 16.12 14.28

5 Angle of

repose(º)

33.42 34.75 34.24 33.60

Pre compression parameters of ATC: SAC co-crystal (SG) granules

13 March 201551

Sr. No. Parameters F13 F14 F15 F16

1 Bulk

density(g/ml)

0.544 0.568 0.564 0.532

2 Tapped

density(g/ml)

0.645 0.658 0.661 0.629

3 Hausner’s ratio 1.18 1.15 1.17 1.18

4 Compressibility

index

15.85 13.67 14.67 15.42

5 Angle of

repose(º)

31.42 32.33 33.56 32.33

Pre compression parameters of ATC: UREA co-crystal (SG) granules

13 March 201552

Evaluation of post compression parametersSr. No. Batch Hardness

(kg/cm2)

Friability

(%)

Thickness

(mm)

Weight

variation(mg)

Disintegration

time (min.)

Drug content

(%)

1 F1 5.0 0.481 2.95±0.01 200.25±1.90 15.30 99.1

2 F2 5.50 0.466 3.00±0.02 199.50±1.56 15.50 100.2

3 F3 5.50 0.524 2.70±0.04 201.15±1.92 15.60 98.4

4 F4 4.50 0.582 2.98±0.01 200.50±1.62 15.00 100.1

5 F5 5.0 0.524 2.99±0.01 199.25±1.36 18.30 99.5

6 F6 5.50 0.550 2.95±0.04 198.50±1.58 18.00 99.4

7 F7 5.30 0.542 2.98±0.01 202±1.92 17.30 100.2

8 F8 5.20 0.426 3.00±0.02 200.25±1.90 17.00 99.1

9 F9 5.30 0.424 2.96±0.03 200±1.72 17.00 98.5

10 F10 5.0 0.422 3.00±0.01 201.75±1.85 18.30 98.8

11 F11 5.30 0.426 2.97±0.05 199.90±1.80 16.60 99.2

12 F12 5.0 0.532 3.00±0.02 201.25±1.88 17.00 98.1

13 F13 5.5 0.563 2.95±0.06 198.25±1.70 18.30 98.2

14 F14 5.20 0.542 2.98±0.02 200.50±1.80 16.00 99.1

15 F15 5.5 0.550 3.00±0.01 198.90±1.55 16.30 98.5

16 F16 5.5 0.528 2.96±0.04 199.50±1.58 16.60 98.8

13 March 201553

In-vitro drug dissolution studies for ATC co-crystal tablets.

Fig19-Comparative in-vitro drug

dissolution profiles for ATC: UREA co-

crystal tablets (SE)

Fig20- Comparative in-vitro drug

dissolution profiles for ATC: SAC

co-crystal tablets (SE)

13 March 201554

Fig22-Comparative in-vitro drug

dissolution profiles for ATC: UREA

co-crystal tablets (SG)

Fig21- Comparative in-vitro drug

dissolution profiles for ATC: SAC co-

crystal tablets (SG)

13 March 201555

Comparison with Marketed product

Fig23- Comparative in-vitro drug dissolution profiles for Optimized

formulation (F4) and Marketed product

13 March 201556

Stability study of optimized formulation

Condition Physical

Appearance

Dissolution

(In 30 min)

Assay (%)

Initial

40°C/75% RH

(HDPE)

White 98.73 100.1

1 month

40°C/75% RH

(HDPE)

White 97.2 100.3

CONCLUSION

13 March 2015

57

13 March 2015

58

Four co-crystals of ATC were prepared using two different co-crystal formers,

saccharin and urea and two methods of preparation, solvent evaporation and

solid grinding.

The co-crystals showed improved solubility and in turn higher dissolution rate

than the pure drug indicating co-crystal approach as a novel and valuable means

to alter the physical characteristics of an API without chemical modification.

Sixteen formulations of ATC co-crystal tablets were successfully formulated by

wet granulation technique.

13 March 201559

The prepared tablets were evaluated for both pre and post compression

parameters .

Based on the results, ATC: SAC co-crystal and solvent evaporation method

was found to be more suitable than ATC: UREA co-crystal and solid grinding

method.

Amongst all 16 formulations of Atorvastatin Calcium co-crystal tablets,

formulation F4 was found to be superior.

The in-vitro drug release of optimized formulation was 98.03% in 30min with

an average hardness of 4.5kg/cm2.

13 March 201560

• The optimized formulation (F4) was also compared with marketed tablets of

Atorvastatin Calcium .

• From the findings, it may be concluded that the formulated tablets of

Atorvastatin Calcium co-crystals showed improved solubility characteristics

and in-vitro drug release profile as compared to pure ATC. This in turn may be

responsible for achieving higher oral bioavailability and better therapeutic

effect.

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13 March 2015

61

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