Excipients for orally disintegrating · PDF fileExcipients for orally disintegrating tablets. Pharmtechprom 2014, November 26-27 ... Tablet weight 200.0 mg *same formulation also applicable

Nadezhda Romanova

Technical Sales Manager

Pharma Ingredients & Services

Excipients for orally disintegrating

tablets

Pharmtechprom 2014, November 26-27

Introduction ODTs

General recommendations

Source: Global Product Management, Pharma Ingredients & Services, BASF SE, Lampertheim, Germany

FDA recommendations

Tablets that disintegrate / dissolve in the oral cavity

Disintegration time is less than 30 seconds

Maximum tablet weight: 500 mg

Recommended tablet characteristics

Disintegration: 10 – 30 seconds

Disintegration: max. 40 seconds

Crushing strength: 30 – 60 N

Crushing strength: min. 20 N

Crushing strength: max. 80 N

Friability: low (<0.5%)

Friability: more preferably <0.25%)

Conclusion

Tablet sizes: 50 – 500 mg

Tablet sizes: max. ~800 mg

API content: 0.1 to 30 wt.%

API content: max. 60 wt.%

26.11.2014 2


Introduction

Developing an orally dispersible tablet

Source: Th. Cech, European Pharma Application Lab, BASF SE, Ludwigshafen, Germany

Ready-to-use solution

Ludiflash®

one process step

easy to use

short development times

limited formulation variability

regular process safety

Direct compression

various excipients

one process step

very difficult to formulate

long development times due to several hurdles (e.g. flow characteristics)

moderate formulation variability

low process safety

Granulation + tabletting

various excipients and processes

two process steps

easy to formulate

regular development times

huge variability of formulations

high process safety

26.11.2014 3


Introduction Ludiflash®

Composition and characteristics


Ludiflash® is prepared by a patented and validated process in accordance with

cGMP-guidelines. Its properties are superior to the simple physical mixture.

Excipient Quantity Function Reg. status

D-Mannitol 90% filler, slightly sweet taste EP, USP, JP

Kollidon® CL-SF 5% disintegrant EP, USP, JPE

Kollicoat® SR 30D 5% water-insoluble binder,

accelerates the disintegration EP, USP

Regulatory

US-DMFs (Type IV): Ludiflash® (#20960), Kollicoat® SR 30D (#15055)

Europe and US: Each ingredient is monographed

Quality & Regulatory Product Information package (Q&R PI)

26.11.2014 4





Ingredients Granule

(Ludiflash®) ODT

Fine distribution of ingredients good hardness

High porosity quick penetration of water

quick action of disintegrant

short disintegration time

-H2O

blending,

drying

Kollicoat SR 30 D

(aq. dispersion)

Mannitol Kollidon® CL-SF

+ API

+ lubricant

+Kollidon® CL-SF

as extra granular

disintegrant

blending,

compression

26.11.2014 5





Parameter Result

(average value)

Bulk density 400 – 500 g/l

Tap density 500 – 650 g/l

Particle size

(D4,3) 170 – 210 µm

Span ~ 3.5 – 4.0

Particle size distribution of Ludiflash®

0

20

40

60

80

100

0,00

1,00

2,00

3,00

4,00

5,00

1,0 10,0 100,0 1 000,0

Dis

trib

uti

on

[%

]

Vo

lum

e [

%]

Particle size [µm]

Volume Distribution

26.11.2014 6


Formulating Ludiflash® - case studies

Loperamide HCl 2 mg ODT formulation


Formulation

Ingredient Supplier Function Amount

Loperamide.HCl Select Chemie API 2.0 mg

Ludiflash® BASF Matrix 93.5 mg

Kollidon® CL-SF BASF Disintegrant 1.0 mg

Chocolate aroma Symrise Flavor 1.5 mg

Sodium stearyl fumarate JRS Pharma Lubricant 2.0 mg

Tablet weight 100.0 mg

Manufacturing

All components were blended in a Turbula free fall blender for 10 minutes, passed through a

sieve with a mesh size of 0.8 mm and compressed into 7 mm biconvex tablets at 3.9 kN

26.11.2014 7



Loperamide HCl 2 mg ODT properties


Parameter Result

Hardness 7 mm biconvex tablets

30 N

Friability < 0.1%

Disintegration time Phosphate buffer pH 7.2

11 s w/o additional Kollidon CL-SF: 20 s

Dissolution 0.01 N HCl, 100 rpm

94.7% after 30 min

Taste Slightly bitter

Content uniformity Passes the compendial test

(max. +/-3.9%)

Weight uniformity Passes the compendial test

(max. +/-1.2%)

26.11.2014 8



Loratadine 10 mg ODT formulation


Formulation

Ingredient Supplier Function Amount

I

Loratadine* Select Chemie API 10.0 mg


Saccharin-Sodium Merck Sweetener 0.3 mg

II Kollidon® 25 BASF Binder 1.0 mg

III


Peppermint aroma Bell Flavor 3.0 mg

Magnesium stearate Baerlocher Lubricant 4.0 mg


*same formulation also applicable for Cetirizine

Manufacturing

The components of I were granulated with a 6.5% aqueous solution of II (Glatt GPC G3 fluid bed granulator,

atomizing pressure 0.5 bar, inlet air 45-50 °C); resulting granules were blended with III in a Turbula blender

for 10 min, passed through a 0.8 mm sieve and compressed into 8 mm flat tablets at 2.8 kN.

26.11.2014 9



Loratadine 10 mg ODT properties


Parameter Result

Hardness 8 mm flat tablets

37 N

Friability < 0.25%

Disintegration time Phosphate buffer pH 7.2

38 s*

Dissolution 0.01 N HCl, 50 rpm

98.8% after 10 min

Content uniformity Passes the compendial test

Weight uniformity Passes the compendial test

*Disintegration time in the mouth lower by approx. 5 seconds;

can be further reduced by 5-10 sec. after addition of 1% Kollidon CL SF

26.11.2014 10



Ambroxol 20 mg Lozenges – Properties


Formulation

Ingredient Function Amount

Ambroxol API 20.0 mg

Ludiflash® Matrix 1219.0 mg

Splenda Sucralose Sweetener 1.5 mg

Flavor mixture Taste masking 7.5 mg

PRUV® Lubricant 52.0 mg


Manufacturing

All components were blended in a Turbula free fall blender for 10 minutes, passed

through a sieve with a mesh size of 0.8 mm and compressed into 16 mm flat tablets at

4 kN and 40 rpm

26.11.2014 11



Ambroxol 20 mg Lozenges – Properties


Parameter Result

Hardness 16.0 mm flat tablets

267 N

Friability 0.06%

Disintegration time water

242 s

Hardness and disintegration time are unacceptable for

ODTs but very good for Lozenges

26.11.2014 12


Introduction



Ready-to-use solution

Ludiflash®

one process step

easy to use

short development times

limited formulation variability

regular process safety

Direct compression

various excipients

one process step

very difficult to formulate

long development times due to several hurdles (e.g. flow characteristics)

moderate formulation variability

low process safety

Granulation + tabletting

various excipients and processes

two process steps

easy to formulate

regular development times

huge variability of formulations

high process safety

26.11.2014 13


Introduction



In regard to line extensions or improving administration convenience orally

disintegrating tablets have become a popular dosage form over the last years.

Nowadays, the formulator has some ready-to-use aids on hand, allowing quick

and simple drug formulation.

However, not all drugs can be processed as direct compressible formulation,

either because of their poor flow characteristics or due to their poor

compressibility. As a result, granulation processes need to be applied to gain

compressible blends.

The aim of this work was to investigate the performance of various wet binders

onto the properties of the agglomerates, deriving from a high shear granulation

process. Furthermore, the impact of the formulation on the disintegration

characteristics was investigated.

A further aim of this study was the comparison of the performance of various

disintegrants in a set ODT formulation.

26.11.2014 14


Selecting the best binder

Binder overview

Source: Th. Agnese, Th. Cech, European Pharma Application Lab, BASF SE, Ludwigshafen, Germany

Preparation binder solution

Binder applied as aqueous solution

Binder content (water) 10.0-14.3%

Binder content (granules) 2%

Granulation

Equipment Diosna P 1/6

Batch size 600 g

Impeller speed 200 rpm

Chopper speed 2,000 rpm

Processing

0.5 min: powder homogenisation

2.0 min: binder addition

3.0 min: granulation time

Wet sieving 1.6 mm

Drying method tray

Temperature room temperature

Humidity unconditioned

Drying time 48 h

Dry sieving 0.8 mm

Optimal amount of water had to be found for each binder to

avoid over-wetting. Corn starch showed high viscosity &

shear thinning behaviour.

Corn starch offers good binding properties at

concentration of 2% in final granules. Therefore, it is

used as benchmark.

Binder Concentration of solution

[%]

Corn starch* 10.0

Kollidon® 25** 14.3

Kollidon® VA64** 14.3

Kollicoat® IR** 10.0

Kollidon® 90** 12.4

*corn starch dissolved in water at 85°C (~5 min)

**other binders dissolved at room temperature

26.11.2014 15



Binder: corn starch


Viscosity of the polymer solution is a crucial and important parameter when selecting a binder

for high shear granulation processes. Solutions containing the synthetic polymers used in this

investigation led to low or moderate viscosities whereas starch was prepared with hot water

(80°C) resulting in a paste.

Dynamic viscosity (25°C, PP60, n=3),

aqueous solution of 10% corn starch

• Excellent binding properties

• Low priced

• Common in the African market

Advantages

• Must be dissolved under heat

• Impact of dissolving procedure on resulting viscosity

Disadvantages

1,0E+03

2,0E+03

3,0E+03

4,0E+03

5,0E+03

50 100 150 200 250 300 350

Vis

co

sit

y [

mP

as]

Shear rate [1/s]

26.11.2014 16



Particle size distribution


Cumulative particle size distribution

as function of binder

The binders can clearly be distinguished. PSD reveals the

lowest binding efficiency for Kollidon® VA64, followed by

Kollidon® 25, Kollicoat® IR and Kollidon® 90F. The strongest

and also largest agglomerates were gained with corn starch.

Formulation

Filler lactose

GranuLac® 230 98.0%

Binder 2.0%





Granulation


Batch size 600 g



Processing




Wet sieving 1.6 mm

Drying method tray



Drying time 48 h

Dry sieving 0.8 mm

0,08 0,17 0,18 0,15

0,10

0,52

0,54 0,58

0,52

0,51

0,40

0,29 0,24

0,33 0,39

0,0

0,2

0,4

0,6

0,8

1,0

x'=368 µm x'=306 µm x'=289 µm x'=323 µm x'=351 µm

corn starch Kollidon® 25 Kollidon® VA64 Kollicoat® IR Kollidon® 90F

Cu

mu

lati

ve p

art

icle

siz

e d

istr

ibu

tio

n [

-]

>355 µm

125-355 µm

<125 µm

26.11.2014 17



Strength of the formed granules


Friability of granules

as function of binder

Formulation

Filler lactose

GranuLac® 230 98.0%

Binder 2.0%





Granulation


Batch size 600 g



Processing




Wet sieving 1.6 mm

Drying method tray



Drying time 48 h

Dry sieving 0.8 mm

Friability test reveals the lowest binding efficiency for

Kollidon® VA64, followed by Kollidon® 25, Kollicoat® IR and

Kollidon® 90F. The strongest and also largest agglomerates

were gained with the binder corn starch.

0

20

40

60

80

0 5 10 15

Fri

ab

ilit

y [

%]

Testing time [min]

Corn Starch

Kollidon® 25

Kollidon® VA64

Kollicoat® IR

Kollidon® 90F

26.11.2014 18



Disintegration time of tablets without disintegrants


Disintegration time of tablets without disintegrant

(tensile strength 1.0-1.2 N/mm²)

Formulation

Granules 99.5%

Mg-stearate 0.5%

Granulation


Batch size 600 g



Blender

Equipment Turbula T2C

Time (lubricant) 2 minutes

Tabletting

Punch shape round, flat faced

Diameter 8 mm

Tabletting speed 20 tabl./min

Testing

Tablet characteristics

Equipment Sotax HT100

Samples n=20

Disintegration

Equipment Erweka ZT74

Media water, pH 7.0

Temperature 37°C, 1 K

Samples n=6

Comparing tablets of same tensile strength (0.9-1.0 N/mm²),

stronger granules led to longer disintegration time. Ag-

glomerates containing corn starch resulted in disintegration

times of about 30 s without any additional disintegrant.

32 63 55 104 364 0

50

100

150

200

250

300

350

400

450

500

Corn starch Kollidon® 25 Kollidon® VA64 Kollicoat® IR Kollidon® 90F

Dis

inte

gra

tio

n t

ime [

s]

26.11.2014 19



Disintegration time of tablets with disintegrants


Disintegration time of tablets without disintegrant

(tensile strength 1.0-1.2 N/mm²)

Formulation

Granules 89.5%

Kollidon® CL-SF 10.0%

Mg-stearate 0.5%

Granulation


Batch size 600 g



Blender



Tabletting


Diameter 8 mm


Testing



Samples n=20

Disintegration


Media water, pH 7.0


Samples n=6

As soon as a disintegrant was added to the tabletting blend

(10% Kollidon® CL-SF), disintegration times of all tablets

containing synthetic polymers were below 30 seconds as

well.

10 11 11 23 0

5

10

15

20

25

30

Kollidon® 25 Kollidon® VA64 Kollicoat® IR Kollidon® 90F

Dis

inte

gra

tio

n t

ime [

s]

26.11.2014 20



Summary


Even though starch paste offered distinct disadvantages in regard to its

application, it offered some benefits regarding the resulting agglomerates.

• Firstly, strength of the formed agglomerates was high (low friability) allowing

good blending and pro-cessing,

• and secondly, disintegration time of the tablets was low, even without

disintegrant in the formulation.

Solutions of synthetic polymers were easier (and safer) to prepare (no heated

water) and easier to process (low viscosities). But, tablet formulations required

some disintegrant to allow quick disintegration.

26.11.2014 21


Selecting the best disintegrant

Introduction


An ODT administration calls for fast disintegrating dosage forms offering a

pleasant mouth-feel to gain patient’s compliance. Hence, the selection of the

disintegrant is crucial for the success of the final product. A further aim of this

study was therefore to compare the performance of various disintegrants in a set

ODT formulation.

Generally, the characteristic of a tablet is strongly impacted by the disintegrant.

Tensile strength and friability for instance as essential parameters are markedly

influenced by particle size of the disintegrant chosen whereas smaller particles

lead to tablets of higher strength. As regards to the ODT application, the texture

the disintegrated tablet presented to the tongue is worth noting.

In this regard, the latter characteristic is influenced by the wetted and swollen

material whereas tensile strength is impacted by the particle size of the dry

powder.

26.11.2014 22



Typical particle size distribution of disintegrants

Source: F. Bang, Th. Cech, European Pharma Application Lab, BASF SE, Ludwigshafen, Germany

Typical particle size distribution of different disintegrants,

determined via laser diffraction


Equipment Malvern Mastersizer 2000

Samples n=3

PSD values

Kollidon® CL

d0.1 10.8 (dry) / 18.5 (wet)

d0.5 47.8 (dry) / 94.0 (wet)

d0.9 166.8 (dry) / 249.2 (wet)

D4.3 70.5 (dry) / 116.0 (wet)

Kollidon® CL-F

d0.1 5.8 (dry) / 15.1 (wet)

d0.5 15.6 (dry) / 39.0 (wet)

d0.9 45.7 (dry) / 116.0 (wet)

D4.3 22.0 (dry) / 57.1 (wet)

Kollidon® CL-SF

d0.1 3.7 (dry) / 9.0 (wet)

d0.5 10.5 (dry) / 31.7 (wet)

d0.9 28.7 (dry) / 71.9 (wet)

D4.3 16.5 (dry) / 36.7 (wet)

Kollidon® CL-M

d0.1 0.9 (dry) / 2.0 (wet)

d0.5 4.2 (dry) / 5.3 (wet)

d0.9 7.8 (dry) / 10.3 (wet)

D4.3 4.4 (dry) / 5.8 (wet)

According to this, Kollidon® CL-M appears to be a promising

candidate. But this grade is micronised and therefore lost its

power to act as a strong disintegrant. Therefore,

Kollidon® CL-SF was selected for this investigation.

0,00

2,00

4,00

6,00

8,00

10,00

0 1 10 100 1 000

Vo

lum

e [

%]

Particle size [µm]

Kollidon® CL (dry)

Kollidon® CL (wet)

Kollidon® CL-F (dry)

Kollidon® CL-F (wet)

Kollidon® CL-SF (dry)

Kollidon® CL-SF (wet)

Kollidon® CL-M (dry)

Kollidon® CL-M (wet)

26.11.2014 23



Typical particle size distribution of disintegrants

Source: F. Bang, Th. Cech, European Pharma Application Lab, BASF SE, Ludwigshafen, Germany

Typical particle size distribution of different disintegrants,

determined via laser diffraction


Equipment Malvern Mastersizer 2000

Samples n=3

PSD values

Polyplasdone® XL

d0.1 29.1 (dry) / 56.3 (wet)

d0.5 127.7 (dry) / 182.8 (wet)

d0.9 345.9 (dry) / 453.2 (wet)

D4.3 161.1 (dry) / 223.6 (wet)

Polyplasdone® XL-10

d0.1 7.7 (dry) / 9.5 (wet)

d0.5 20.8 (dry) / 32.2 (wet)

d0.9 49.3 (dry) / 75.4 (wet)

D4.3 26.1 (dry) / 40.6 (wet)

Ac-Di-Sol®

d0.1 17.9 (dry) / 17.4 (wet)

d0.5 41.7 (dry) / 78.7 (wet)

d0.9 100.1 (dry) / 145.8 (wet)

D4.3 51.7 (dry) / 83.9 (wet)

Explotab®

d0.1 22.9 (dry) / 49.0 (wet)

d0.5 43.8 (dry) / 116.6 (wet)

d0.9 76.7 (dry) / 226.7 (wet)

D4.3 47.1 (dry) / 128.2 (wet)

As second cross-linked PVP grade Polyplasdone® XL-10

was chosen. Furthermore, Ac-Di-Sol® and Explotab® were

used, even though both products presented very

uncomfortable sand in the mouth sensation.

0,00

2,00

4,00

6,00

8,00

10,00

0 1 10 100 1 000

Vo

lum

e [

%]

Particle size [µm]

Polyplasdone® XL (dry)

Polyplasdone® XL (wet)

Polyplasdone® XL-10 (dry)

Polyplasdone® XL-10 (wet)

Ac-Di-Sol® (dry)

Ac-Di-Sol® (wet)

Explotab® (dry)

Explotab® (wet)

26.11.2014 24



Tensile strength of tablets containing different disintegrants


Tensile strength of placebo tablets as function of

disintegrant and compression force

Formulation

Granules (lactose, starch) 94.5%

Disintegrant 5.0%

Mg-stearate 0.5%

Granulation


Batch size 600 g



Blender



Tabletting


Diameter 8 mm


Testing



Samples n=20

Disintegration


Media water, pH 7.0


Samples n=6

A clear functionality of TS on CF was found. Adding a dis-

integrant hardly changed or even decreased tablet strength.

Differently for Kollidon® CL-SF with resulting TS higher

compared to the disintegrant-free formulations.

0,0

0,5

1,0

1,5

2,0

2,5

0,0 2,0 4,0 6,0 8,0

Ten

sil

e s

tren

gth

[N

/mm

²]

Compression force (upper punch) [kN]

AcDiSol®

Explotab®

Kollidon® CL-SF

Polyplasdone® XL10

without disintegrant

26.11.2014 25



Disintegration time of tablets containing different disintegrants


Tensile strength of placebo tablets as function of

disintegrant and compression force

Formulation

Granules (lactose, starch) 94.5%

Disintegrant 5.0%

Mg-stearate 0.5%

Granulation


Batch size 600 g



Blender



Tabletting


Diameter 8 mm


Testing



Samples n=20

Disintegration


Media water, pH 7.0


Samples n=6

Although TS was found to be high, these tablets offered the

shortest disintegration time of all formulations. And even

more interesting, latter values were always found at merely

about 10 s independent of the compression force applied.

0

10

20

30

40

50

60

0,0 0,5 1,0 1,5 2,0 2,5

Dis

inte

gra

tio

n t

ime [

s]

Tensile strength [N/mm²]

AcDiSol®

Explotab®

Kollidon® CL-SF

Polyplasdone® XL10

without disintegrant

26.11.2014 26



Summary


Several advantages can be utilised when employing Kollidon® CL-SF as

disintegrant in ODT tabletting formulations:

• firstly, it presents a superior mouth sensation due to its small particle size,

• secondly, it leads to tablets of high tensile strength,

• and thirdly, it allows very fast disintegration independent of compression

force applied.

26.11.2014 27


Case study on loperamide and cetirizine

Introduction, formulation overview (Loperamide HCl)


Loperamide HCl – Formulation Content

[%]

GranuLac® 230 granules (2% starch) 87.5

Kollidon® CL-SF 10.0

Loperamide HCl 2.0

Mg stearate 0.5

Scanning Electron Microscopy

SE, 5 kV


[%]



Loperamide HCl 2.0

Corn Starch (applied as 4.8% solution) 2.0

Extragranular API / disintegrant


26.11.2014 28



Introduction, formulation overview (Cetirizine HCl)


Cetirizine HCl – Formulation Content

[%]



Cetirizine HCl 5.0

Mg stearate 0.5

Scanning Electron Microscopy

SE, 5 kV


[%]



Cetirizine HCl 5.0




26.11.2014 29



Introduction, formulation overview (ext.)


Extragranular

Compression of granulated GranuLac® with active &

disintegrant in outer phase

Granulation


Batch size 600 g



Blender


Sieving w=0.8


Tabletting


Diameter (loperamide) 7 mm

Tablet mass (loperamide) 100 mg

Diameter (cetirizine) 8 mm

Tablet mass (cetirizin) 200 mg


Testing



Samples n=20

Disintegration


Media water, pH 7.0


Samples n=6


[%]



Loperamide HCl 2.0

Mg stearate 0.5


[%]



Cetirizine HCl 5.0

Mg stearate 0.5

26.11.2014 30



Introduction, formulation overview (int.)


Intragranular

Granulation of active & disintegrant with lactose. Followed

by compression of achieved granules.

Granulation


Batch size 600 g



Blender


Sieving w=0.8


Tabletting


Diameter (loperamide) 7 mm

Tablet mass (loperamide) 100 mg

Diameter (cetirizine) 8 mm

Tablet mass (cetirizin) 200 mg


Testing



Samples n=20

Disintegration


Media water, pH 7.0


Samples n=6


[%]



Loperamide HCl 2.0



[%]



Cetirizine HCl 5.0


99.5%

+ 0.5% MgS

99.5%

+ 0.5% MgS

26.11.2014 31



Tablet characteristics, tensile strength


Almost no differences between external & internal

application of active & disintegrant.

A yellowish discolouration for the Cetirizine formulation

could be observed (quickly for ext. later also for int.).

Formulation (Loperamide)

Loperamide HCl (int./ext.) 2.00%

GranuLac® 230 (int.) 87.75%

Kollidon® CL-SF (int./ext.) 10.00%

Maize starch (int.) 1.75%

Mg-stearate (ext.) 0.50%

Formulation (Cetirizine)

Cetirizine HCl (int./ext.) 5.00%





Granulation


Batch size 600 g



Blender


Sieving w=0.8


Tabletting


Diameter (lop./cet.) 7/8 mm

Tablet mass (lop./cet.) 100/200 mg


Tablet testing


Samples n=20

Tensile strength of tablets

as function of compression force

0,0

1,0

2,0

3,0

4,0

0,0 2,0 4,0 6,0 8,0

Ten

sil

e s

tren

gth

[N

/mm

²]

Compression force (upper punch) [kN]

Loperamide ext. Loperamide int. Cetirizine ext. Cetirizine int.

26.11.2014 32



Tablet characteristics, disintegration


Only the formulation containing Cetirizine in its internal

phase showed slightly longer disintegration times. All other

formulation offered quick disintegration without effect of

compression force.

Tensile strength of tablets

as function of compression force

Formulation (Loperamide)






Formulation (Cetirizine)






Granulation


Batch size 600 g



Blender


Sieving w=0.8


Tabletting





Tablet testing


Media water, pH 7.0


Samples n=6

0

10

20

30

40

50

60

0,0 0,5 1,0 1,5 2,0 2,5 3,0

Dis

inte

gra

tio

n t

ime [

s]

Tensile strength [N/mm²]

Loperamide ext. Loperamide int. Ceterizine ext. Cetirizine int.

26.11.2014 33



Stability, tensile strength


Both Loperamide formulations are very stable and don’t

present any significant change during stability testing.

The Cetirizine formulations loose TS at 40°C/75% r.h.,

whereas int. and ext. can be distinguished.

Stability testing (ICH conditions)

tensile strength

Formulation 1






Formulation 1






Tabletting





Storage

Packaging material PE container

Condition closed

Size 100 mL

Testing


Samples n=20

Equipment ERWEKA ZT74

Media water, pH 7.0


Samples n=6

Equipment Mettler PM1200

Temperature 85°C

0,0

0,5

1,0

1,5

2,0

2,5

Loperamide int. Loperamide ext. Ceterizine int. Ceterizine ext.

Ten

sil

e s

tren

gth

[N

/mm

²]

Start

1 month (40°C/75%)

3 months (40°C/75%)

6 months (40°C/75%)

3 months (30°C/70%)

6 months (30°C/70%)

6 months (25°C/60%)

26.11.2014 34



Stability, disintegration time


The disintegration characteristics of both Loperamide

formulations were excellent and didn’t alter during stability.

The Cetirizine formulations disintegrated slow, and

disintegration time slightly prolonged during stability.


disintegration time

0

10

20

30

40

50

60


Dis

inte

gra

tio

n t

ime [

s] Start

1 month (40°C/75%)

3 months (40°C/75%)

6 months (40°C/75%)

3 months (30°C/70%)

6 months (30°C/70%)

6 months (25°C/60%)

Formulation 1






Formulation 1






Tabletting





Storage


Condition closed

Size 100 mL

Testing


Samples n=20


Media water, pH 7.0


Samples n=6


Temperature 85°C

26.11.2014 35



Stability, water up-take


With all formulations a distinct water up-take can be

detected over time. This is most likely due to the Kollidon®

CL-SF content in the formulation.


water up-take (mass increase)

0,0

0,3

0,6

0,9

1,2

1,5


Wate

r u

p-t

ake [

%] 1 month (40°C/75%)

3 months (40°C/75%)

6 months (40°C/75%)

3 months (30°C/70%)

6 months (30°C/70%)

6 months (25°C/60%)

Formulation 1






Formulation 1






Tabletting





Storage


Condition closed

Size 100 mL

Testing


Samples n=20


Media water, pH 7.0


Samples n=6


Temperature 85°C

26.11.2014 36



Stability, loss on drying


Interestingly, even though a mass increase was detected

over time, this result does not correspond with the LoD test.

Actually, the detected LoD value decreased over time.


impact on loss on drying (at 85°C)

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0


Lo

ss o

n d

ryin

g [

%]

Start

1 month (40°C/75%)

3 months (40°C/75%)

6 months (40°C/75%)

3 months (30°C/70%)

6 months (30°C/70%)

6 months (25°C/60%)

Formulation 1






Formulation 1






Tabletting





Storage


Condition closed

Size 100 mL

Testing


Samples n=20


Media water, pH 7.0


Samples n=6


Temperature 85°C

26.11.2014 37


Conclusion

Pros and cons


Pros

cheaper in regard to excipients used

more flexibility in regard to formulation

more flexibility on how the API is incorporated

Cons

more expensive in regard to processing

more equipment involved (investment, production timeline, cleaning)

more complex formulation

higher development efforts (e.g. validation, QbD)

26.11.2014 38

Thank you!

Nadezhda Romanova

Technical Sales Manager

Pharma Ingredients & Services

OOO BASF

Phone: + 7 (495) 231-72-27

Mobile: + 7 (916) 304-77-15

E-mail: [email protected]

Web-site: www.pharma-ingredients.basf.com

Pharmtechprom 2014, November 26-27 26.11.2014 39

Documents

Excipients for orally disintegrating · PDF fileExcipients for orally disintegrating tablets. Pharmtechprom 2014, November 26-27 ... Tablet weight 200.0 mg *same formulation also applicable