New surfactants in wet ball milling and an innovative embedding … · of solids, semi solids and...

New surfactants in wet ball milling and an innovative

embedding of Nanocrystals into a granulate matrixby Dr. Matthias Rischer, Director Drug Delivery & Innovation Projects,

Losan Pharma

Introduction of Losan Pharma

➢ Losan Pharma is a pharma-technology company focused on the development

and manufacturing of innovative medicinal products with improved API performance

and/or convenient application.

➢ Based on our specific development know-how and on our platform

technologies we provide solutions to challenging tasks with a view to improved

API stability, superior bioavailability, designed delivery and increased patient

compliance for standard and high-potent APIs.

➢ We are the one-stop-shop for development and commercial manufacturing

services for Europe, the Americas and Asia to support our customers in marketing

value-added products for the benefit of their patients and customers

Losan Pharma Sites

Neuenburg Site

▪ manufacturing and packaging

of solids, semi solids and

liquids

▪ contract development

▪ clinical trial supply

▪ QC and release of FP

▪ storage & stability testing

▪ starting material sampling,

testing and release

Eschbach Site

▪ primary and secondary

packaging

▪ 11 cabinets

▪ stick packs, blisters and

sachets

▪ QC of FP

Frankfurt Site

▪ contract development for

HPAPIs

▪ solid, lipids and

parenteral formulations

▪ quality control testing

APIs up to OEL class 3b (OEB 4) APIs up to OEL class 4 (OEB 5)APIs up to OEL class 3b (OEB 4)

Screening phase – the Losan

approach

Development of a new innovative efficient screening system for early drug development

with a high predictability (Dual Centrifugation; Zentrimix 380R Hettichlab) has

been completed:

Source: Hagedorn et. al. Int. J. Pharm. 530 (2017), 79-88

Screening phase- the

Nanocrystal effect

10 µm 1 µm 100 nm 20 nm >> 1 µm

PARTICLE SIZE

Source: Drug Delivery Strategies for poorly water soluble drugs, Wiley, 2013

10 µm 1 µm 100 nm 20 nm >> 1 µm

Re-crystallisation to large crystals

>> 1 µm

Static initiation of re-crystallisation

thermodynamic solubilitythermodynamic solubility

kinetic solubility

Complete dissolution of

crystals (oversaturation/

molecular solubility)S

OLU

BIL

ITY

Screening – DoE example of

Fenofibrated(90) [nm]

PVP VA 64PVP K25HPMC

DO

SS

SDS

Twee

n 8

0

amount of Copolymer [%]

amo

un

t o

f Su

rfac

tan

t [%

]

The need for new surfactants

There is a need for new stabilising surfactants as one of the golden standards

SDS is not suitable for parenteral applications and can cause side effects in

oral treatments if dosed too high. As a consequence new surfactants have

been developed with improved tox-properties:

N-Decanoyl-amino acids

D.R. Perinelli et. al. Colloids & Surfaces 492 (2016) 38-46

D.R. Perinelli et. al. Eur. J. Ph. & Bioph., 109 (2016) 93-102

Rhamnolipids (glycolipids produced by Pseudomonas aeruginosa as a

mixture of mono and di-rhamnolipids; available by Merck in 90% purity):

CMC (tensiometric)

example of a di-rhamnolipidSource: D.R. Perinelli, E. J. Pharm & Biopharm. 119

(2017) 419-425



Important physicochemical properties and tox profile:

CMC (tensiometric) Hemolytic assay

Source: D.R. Perinelli et. al. Colloids & Surfaces 492 (2016) 38-46


CMC (tensiometric) Hemolytic assay

Source: D.R. Perinelli et. al. Eur. J. Pharm. & Biopharm., 109 (2016) 93-102

Conclusion: similar CMC (chain length difference) and improved hemolytic assay.

C10-ALA, C10-SER and C10-PRO selected (based also on good MTT, LDH and

TEER values, with best profile for C10-SER).

Reference Model Drug

Patel et. al. published a study for Efavirenz (EFV) Nanosuspensions in which

the following parameters have been found to be optimal (Box-Behnken Design;

mean PSD 320 nm; Zetapotential -32.8 mV)

Rabbit study results API concentration 4.0%,

Polymer concentration (PVP K30) 1.0 %,

Surfactant concentration (SDS) 0.5%,

Milling time 22h (beads 0.4 – 0.7 mm)

(Lyophilisation 24h at -70°C)

aqueous solubility of 9.0 µg/mL

BCS class II

Source: Patel et. al. Drug Dev. Ind. Pharm. 2014, 80-91

Screening results with new

surfactants

Targets of the study:

➢ Evaluate the stabilization effect of new selected surfactants against SDS for

EFV for PSD

➢ Evaluate the concentration effect of EFV in the nanosuspensions

➢ Evaluate the concentration effect of the new surfactants in relation to the

polymer and API concentration

➢ Evaluate the concentration effect of the new surfactants in relation to the

polymer type and API concentration

➢ Run DoEs if possible


surfactants

First step:

10% API loading, bead size 0.1 mm, standard milling time (1.5h), standard

polymer matrix


surfactants

Results for HPC-SL


surfactants

Results for HPMC


surfactants

Results for POLOXAMER 188


surfactants

Second step: 10% (for PVP only)/ 30% API loading, standard bead size

0.3 mm and milling time (1.5 h)

Test

no.

Polymer

type

Polyme

r [%]

Surfactant

type

Surfactan

t

[%]

API conc.

[%]

PSD

(D10)

PSD

(D50)

PSD

(D90)SPAN

E31 HPC-SL 3.0 C10 ALA 0.5 30.0 0.020 0.061 0.195 2.85

E32 HPC-SL 3.0 C10 SER 0.5 30.0 0.020 0.059 0.178 2.70

E33 HPC-SL 3.0 C10 PRO 0.5 30.0 0.020 0.060 0.186 2.77

E34 HPC-SL 3.0Rhamnolipi

d0.5

30.0 0.022 0.075 0.278 3.40

E35 HPC-SL 3.0 SDS 0.5 30.0 0.020 0.058 0.170 2.60

E41 PVP K30 3.0 C10 ALA 0.5 10.0 0.023 0.071 0.225 2.87

E42 PVP K30 3.0 C10 ALA 0.5 30.0 0.021 0.071 0.263 3.41

E43 PVP K30 3.0 C10 SER 0.5 10.0 0.022 0.075 0.280 3.45

E44 PVP K30 3.0 C10 SER 0.5 30.0 4.58 29.6 176 5.79

E45 PVP K30 3.0 C10 PRO 0.5 10.0 0.020 0.061 0.206 3.08

E46 PVP K30 3.0 C10 PRO 0.5 30.0 0.023 0.078 0.281 3.32

E47 PVP K30 3.0Rhamnolipi

d0.5

10.0 0.017 0.044 0.151 3.03

Rhamnolipi 30.0 0.031 0.223 7.14 31

PSD overlay samples E02, E04, E06, E08, E10 (HPC-SL 3.0% / Surfactant 0.5% / API 10%)

PSD overlay samples E31 - E35 (HPC-SL 3.0%, Surfactant 0.5 %, API 30%)


surfactants


surfactants

PSD overlay samples E41, E43, E45, E47, E49 ( PVP K 30 3.0%, Surfactant 0.5%, API 10%)

PSD overlay samples E42, E44, E46, E48, E50 (PVP K 30 3.0% / Surfactant 0.5%/ API 30%)


surfactants

Third step: DoE trial approach with 30% API loading, 2 polymers, 2

surfactants, two concentrations for each, beads 0.3 mm, milling 1.5h

Test

no.

Polymer

typePolymer

Surfactant

type

Surfac-

tantAPI

PSD

(D10)

PSD

(D50)

PSD

(D90)SPAN

Shape of

curveConsistency

[%] [%] [%] [µm] [µm] [µm]

E61 HPC-SL 1.0 C10 ALA 0.1 30.0 n.p. n.p. n.p. n.p. n.p. solid

E62 HPC-SL 3.0 C10 ALA 0.1 30.0 5.00 24.9 109 4.17 multimodal pasty

E63 HPC-SL 1.0 Rhamnolipid 0.1 30.0 n.p. n.p. n.p. n.p. n.p. solid

E64 HPC-SL 3.0 Rhamnolipid 0.1 30.0 0.0328 1.81 38.1 21.0 multimodal viscous

E65 HPC-SL 1.0 C10 ALA 0.3 30.0 2.54 11.1 146 13.0 multimodal viscous

E66 HPC-SL 3.0 C10 ALA 0.3 30.0 0.021 0.065 0.228 3.21 unimodal liquid

E67 HPC-SL 1.0 Rhamnolipid 0.3 30.0 2.06 13.9 236 16.8 multimodal pasty

E68 HPC-SL 3.0 Rhamnolipid 0.3 30.0 0.026 0.127 4.78 37.4 bimodal liquid

E69 HPC-SL 1.0 C10 ALA 0.5 30.0 0.263 24.7 216 8.75 multimodal pasty

E70 HPC-SL 1.0 Rhamnolipid 0.5 30.0 0.025 0.101 2.84 28.0 bimodal liquid

E31 HPC-SL 3.0 C10 ALA 0.5 30.0 0.020 0.061 0.195 2.85 unimodal liquid

E34 HPC-SL 3.0 Rhamnolipid 0.5 30.0 0.022 0.075 0.278 3.40 unimodal liquid

E71 HPC-SL 2.0 C10 ALA 0.3 30.0 0.078 8.35 72.9 8.73 multimodal viscous/pasty

E72 HPC-SL 2.0 C10 ALA 0.3 30.0 1.95 19.5 78.2 3.92 multimodal pasty


surfactants

Test

no.

Polymer

typePolymer

Surfactant

typeSurfactant API

PSD

(D10)

PSD

(D50)

PSD

(D90)SPAN

Shape of

curveConsist.

[%] [%] [%] [µm] [µm] [µm]

E73 HPC-SL 2.0 C10 ALA 0.3 30.0 0.180 10.2 68.6 2.07 multimodal pasty

E76 PVP K30 1.0 C10 ALA 0.1 30.0 4.53 27.0 79.3 2.77 multimodal pasty


E78 PVP K30 1.0 Rhamnolipid 0.1 30.0 2.96 20.8 97.8 4.56 multimodal pasty

E79 PVP K30 3.0 Rhamnolipid 0.1 30.0 3.20 26.0 203 7.70 multimodal pasty

E80 PVP K30 1.0 C10 ALA 0.3 30.0 3.86 24.1 206 8.40 multimodal pasty

E81 PVP K30 3.0 C10 ALA 0.3 30.0 4.81 28.6 104 3.48 multimodal pasty




E85 PVP K30 1.0 Rhamnolipid 0.5 30.0 0.031 0.254 74.0 291 multimodal pasty

E42 PVP K30 3.0 C10 ALA 0.5 30.0 0.021 0.071 0.263 3.41 unimodal liquid

E48 PVP K30 3.0 Rhamnolipid 0.5 30.0 0.031 0.223 7.14 31.0 bimodal liquid


surfactants

Forth step: Increase of polymer concentration, comparison to SDS (same

conditions)

➢ Re-analysis of all stable nanosuspensions (1st to 4th step) after several weeks(ambient temperature) have indicated no change in PSD

➢ Zetapotential of stable nanosupensions in the range of -11 to-33 mV

Polymer type Polymer [%] Surfactant type Surfactant

[%]

D10

[µm]

D50

[µm]

D90

[µm]

PVP K 30 4 Rhamnolipid 0.3 0.055 2.95 33.2

PVP K 30 5 Rhamnolipid 0.3 0.033 0.280 18.8

PVP K 30 4 C10 ALA 0.3 0.023 0.081 0.333

PVP K 30 5 C10 ALA 0.3 0.023 0.079 0.296

PVP K 30 4 SDS 0.3 0.023 0.081 0.337

HPC-SL 4 SDS 0.1 0.023 0.086 0.423

HPC-SL 4 C10 ALA 0.1 8.35 42.7 122

HPC-SL 5 C10 ALA 0.1 0.024 0.088 0.443

HPC-SL 4 Rhamnolipid 0.1 0.028 0.203 12.5



The importance of milling beads

SiLibeads® ZY-P beads (e.g. 0.1 mm) are well quality-controlled in terms of

surface roughness e.g. by laser microscope

Roughness profile

3D-viewLine

roughnessRa

= 0,008 µm

=0,018 µm

Roughness profile

Downprocessing

▪ The stabilization of nanocrystals is very effective by a fluid bed layering

(FBD) process. Further stabilization by surfactants/polymers is needed

during this step

▪ Loading of up to 50% have been achieved successfully, making doses of

500 mg per unit possible

Embedding of Nanocrystals

Results with a fluid bed coating and compression with Mannitol starter

pellets and 30% Naproxen loading using a 20% stabilized Naproxen

nanosuspension


Thermo Fisher Pharma 11 System adapted with liquid side feeding and optional vacuum drying

34 hole die plate extrudate strands dry, sieved granules


Results for extruded granulate

Summary

➢ New tested surfactants resulted in nanocrystal suspensions with unimodal PSDdistributions if sufficient Polymer concentration and the right type of Polymer hasbeen selected

➢ No significant difference between the tested new surfactants have been seen inthe trials

➢ HPC-SL was determined to have the best stabilizing potential

➢ SDS gives lower PSD values compared to the new surfactants if used in the samelow concentration (difference in CMC). Could be compensated by higher polymerconcentrations for new surfactants

➢ DoE trial showed unexpected high variability of PSD data with selected factors (nosurface plots useful)

➢ New surfactants should be further considered for Nanocrystal suspensions and wetball milling and will be subject to an investigation on permeability

➢ New embedding on Nanocrystals by continuous granulation (extruder) gavecomparable results to a Fluid bed drying process and opens new perspectives

Acknowledgments

Nanoteam Losan Pharma

• Dr. Ansgar Bögershausen

• Dr. Martin Hagedorn

• Dominique Di Stefano

• Lena Liebich

• Ampara Spieker

• Doreen Rischkau

• Christine Osterod

Supply of Surfactants & Cooperation

• Diego Romano Perinelli, University of Camerino, Italy

Supply of Zr/Y beads & Cooperation

• Sigmund Lindner, Warmensteinach, Germany

New surfactants in wet ball milling and an innovative embedding … · of solids, semi solids and...

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