14 - 16 May 2013

BioTrinityNewbury, UK For more information please visit: http://www.biotrinity.com

22 - 24 October 2013 CPhI/ICSE Frankfurt, Germany

For more information please visit:http://www.cphi.com/event-calendar

www.tillotts.com

Welcome to the last 2012 edition of our quarterly Newsletter. We are very delighted about the positive feedback regarding our Newsletter during the past period. Within this edition we introduce Solid Form Solutions Ltd., a contract research organisation, which is working with Tillotts Services within a co-promotion agreement. Our technology article profiles the use of Texture Analysis Methods for assessing the impact of lipid based formulations. Also we report about our forthcoming event attendances as well as our staff interview.

Since January 2012 Tillotts Pharma AG has entered a collaboration with Solid Form Solutions (SFS) which is very successful (we refer to our article in the Newsletter 4) and we will continue this relationship. In this issue we are pleased to publish an article of Dr. Stephen Watt (CEO). Many thanks to you, Stephen and your team for this efficient cooperation.

[Dr. Stephen Watt, CEO, Solid Form Solutions Ltd.] Solid Form Solutions Ltd is a contract research organisation (CRO) located just outside Edinburgh in Scotland. The company provides the pharmaceutical industry with salt, polymorph and co-crystal screening services as well as scale-up crystallisation programs. The company also has a very high level of expertise in controlling particle size

and morphology during the crystallization process. The company’s unique selling point is that they have been able to bridge the gaps very successfully between the bench and manufacturing plant.

Issue 7

NEWSLETTER

Acknowledgements: Design by David Anthony, AK Design (Scotland) Ltd.

For more information, please contact us at:

Q: So Hansueli please tell us a little about yourself?

A: I have the big advantage to live with my family here in Ziefen. So my way to work by bicycle is very short. We are living in an old house with a big garden and we have a dog, some chicken and a cock (for the wake up cark). Two of our three children are still living at home as they are continuing their study. By the way, people who can’t pronounce my typical Swiss name just call me Hans. I like driving slow old tractors and also fast new motorbikes.

Q: When did you join Tillotts?

A: In January 2002 I started at Tillotts as production manager.

Q: What is your role within Tillotts?

A: Today I am the Head of Tillotts Services and this includes the departments Contract Services & Business Development, Logistics, Production & Packaging, Engineering and Quality Control. Together with my team, which is the best, we produce several products for our different customers in the necessary quality according the GMP regulations.

Q: What was the biggest challenge for you at Tillotts?

A: In 2009 when the company was for sale, we had a big uncertainty internally and also towards our different customers about the future business. We were able to keep our production volume and our motivation for the daily work. We created and implemented a new business plan for Tillotts Services.

Q: What will be your next big challenge at Tillotts?

A: After my 60th birthday I plan to reduce my working time to 80% and I have to find and train my successor.

Q: Of which project are you most proud?

A: I am very happy to be part of this GMP facility in Switzerland and to produce a set of different products for several big pharmaceutical companies outside Switzerland. Every day, week, month, year we have new tasks and new projects and we are able to complete them in time and in good quality.

Q: Why is Tillotts the best company for you?

A: The Ziefen factory is a small unit and everyone knows all procedures. For all challenges we find the right solution. The whole team is highly motivated to do a good job and to serve our customers with the best service. The equipment is well maintained and we can invest in new machinery. I am very satisfied working in this international team which is part of Tillotts Pharma AG with its headquarters in Rheinfelden and our Japanese parent company, Zeria Pharmaceutical Co. Ltd. in Tokyo.

In this edition Miriam Adler interviews Hansueli Schaub, Head of Tillotts Services

ww

w.tillotts.com T: +41 61 935 28 28

F: +41 61 935 28 29E: services@tillotts.com

Tillotts Pharma AGTillotts ServicesHauptstrasse 274417 ZiefenSwitzerland

Tillotts Services will be represented at the following events during 2013. We would be delighted to meet with you.

Let’s Have Coffee..

The successful collaboration between Tillotts Pharma AG and Solid Form Solutions Ltd. continues

Follow us on LinkedIn:Please join our LinkedIn Group “Tillotts Services” on LinkedIn. We will inform you about several forthcoming events as well as the latest news within Tillotts Services.

See us on YouTube:If you are interested in the Liquid Fill Encapsulation Technology as well as in the manufacturing process of Tillotts Services you have now the opportunity to follow us on YouTube.

picture source: Solid Form Solutions Ltd.

As well as small molecules, SFS have worked on many peptide crystallisation projects that have simplified the purification of these complex materials. Furthermore, SFS has demonstrated the presence of polymorphism in these compounds. The company leads in this area and has supported a number of very successful scale-up campaigns that have seen their clients move rapidly through development. More information can be found at: http://www.youtube.com/watch?v=jKLf_EK0j-w

Solid Form Solutions is also on the “Road to GMP” and by early 2013 expects to have been inspected by the MHRA, allowing the company to release material as part of their client’s GMP campaigns, which will serve to strengthen their combined offering with Tillotts.

SFS see their partnership with Tillotts Pharma as a unique and powerful tool for drug development, providing clients with not just an excellent chemical development program; but, access to the best formulation technologies and strategies in the business.

CEO of SFS, Dr Stephen Watt, says “our partnership with Tillotts Pharma has been an excellent success and we are looking forward to introducing new services that will facilitate and compliment the services of Tillotts further, making drug development even faster and more economical for clients”.

Copyright © Tillotts Pharma AG 2012 www.tillotts.com

Focus on TechnologyWithin this section we aim to profile a technology area related to our business.

In this section we share recent in-house data highlighting the use of Texture Analysis Methods for assessing the impact of lipid based formulations containing critical levels of co-solvents on mechanical properties like elasticity, brittleness and softness of hard shell capsules. In the following the results obtained with two different texture analysis methods have been compared.

Lipid formulations filled into two piece hard shell capsules have gained increasing interest in last two decades due to its proven effect improving the oral bioavailability of compounds with suboptimal physicochemical properties [1]. Hydrophilic co-solvents have been broadly used in Type IV lipid-based drug delivery systems [2]. However, depending on their amount in the lipid formulation, co-solvents might lead to compatibility issues like softness or brittleness of the capsule shell, deformation of the capsules or inducing leakage of the formulations [3]. Therefore, an understanding of critical level of co-solvents influencing the shell integrity of hard capsules is crucial during early pharmaceutical development.

In this investigation model lipid-based formulations containing different levels of co-solvents were used. The effect of three different factors on the mechanical properties of hard shell capsules was investigated, namely the Hydrophilic-Lipophilic Balance (HLB) of the lipidic component, the amount (%) of ethanol as hydrophilic co-solvent, and the relative humidity (% rH) during 2 weeks of storage of the filled capsules. Texture analysis (TA.TXPlus Texture Analyser from Stable Micro Systems®) was used to monitor changes of liquid-filled hard shell capsules. Two texture analysis methodologies (modes) were used, the compression and the force-in tension modes. While the compression mode has been traditionally used for assessing properties of hard shell capsules [4], limited information is available on the force-in-tension mode [3].

The effect of the different factors on the integrity of the capsule shell was investigated using gelatine and hydroxypropylmethylcellulose (HPMC) hard shell capsules. Rather challenging formulations were selected in order to study the mechanical limits of the capsules. Hard gelatine capsules were found to better tolerate the challenging formulations, and therefore were selected for further texture analysis investigations. Table 1 summarizes the correlations between the responses obtained from the two texture analysis methods.

Table 1Correlations between responses obtained by two different texture analysis methods

Figure 5Mean of work of compression responses of the different capsules on storage

Figure 1Compression mode

Figure 2Compression – relaxation diagram

Conclusions

A successful hand-to-hand comparison and a good correlation between the responses from two texture analysis methods was obtained

Texture analysis in compression mode was found to be a suitable tool to assess mechanical changes of hard gelatine capsules

Compression mode was of practical advantage, because liquid-filled capsules can be directly investigated without any previous handling (manipulations)

The laborious emptying and cleaning of capsules needed for force-in-tension mode is not required

Compensating effects of factors like co-solvent level, formulation polarity and environmental humidity can lead to capsules with little mechanical change by texture analysis. Such effects must be considered and corroborated by other techniques (i.e. microscopy) to assure an adequate assessment of the mechanical properties of liquid-filled capsule drug products

References [1] Jannin V., Musakhanian J., Marchaud D. (2008). Approaches for the development of solid and semi-solid lipid-based formulations. Adv Drug Deliv Rev. 17: 734-46.

[2] Mohsin K. (2012). Design of lipid-based formulations for oral administration of poorly water-soluble drug fenofibrate: effects of digestion. AAPS PharmSciTech. 13:637-46.

[3] Mei X. et al. (2006). Use of texture analysis to study hydrophilic solvent effects on mechanical properties of hard gelatine capsules. Int. J. Pharm. 324: 128-135.i

[4] Kuentz M. and Röthlisberger D. (2002). Determination of the optimal amount of water in liquid-fill masses for hard gelatine capsules by means of texture analysis and experimental design. Int. J. Pharm. 236: 145-152.

Figure 1 represents the texture analysis devise used for working in compression mode. A cylindrical plate sensor was used to compress the entire capsules up to a displacement of 1.3 mm (strain range) at a the controlled speed of 0.5 mm/s. Figure 2 shows the responses obtained, namely compression force (N) and the work of compression (N.mm) calculated from the compression – relaxation steps.

For the force-in-tension mode, capsule bodies were mounted on two short rods separated by a distance of 1 mm. One rod was fixed and the other moves upwards with a speed of 0.5 mm/s until bodies were pulled apart (Figure 3). Figure 4 shows a typical force–displacement diagram obtained by force-in-tension mode. The force applied at rupture point or tensile force (N) and the slope of the linear section of the curve or elastic stiffness (N.mm-¹) were recorded.

Figure 3Force-in-tension mode

Figure 4Force–displacement diagram

The work and force of compression obtained from the compression mode did perfectly correlate each other, and also a good correlation of these responses was obtained with the tensile force from the force-in-tension mode. Only the elastic stiffness was found not to correlate with the force and the work of compression (p-value>0.05), the latter being non-destructive to the capsules. Therefore, the focus was set to the compression mode, specifically to work of compression as main response. The effect of three parameters and their possible interactions were investigated. As shown by figure 5 significant differences on the work of compression responses were found among the groups (p < 0.05). As expected, some of the rather challenging formulations clearly caused significant mechanical changes on the capsule shell. However, other capsules were found in the range of control units. Probably in later case, the co-solvent effect on shell brittleness was balanced to some extent by a compensatory effect of the storage humidity that rather softened capsules.

RESPONSES Work of compression Tensile force Elastic stiffness

Force of compression 0.0007 0.011

0.0172

0.3325

0.4271

0.0148

Work of compression

Tensile force

Wor

k of

com

pres

sion

(N.m

m)

contro

l

contro

l 20%

contro

l 40%

contro

l 60%

HLB 9.65: 16%

etOH: 4

0% rH

HLB 15: 4

% et

OH: 40%

rH

HLB 4.3: 16%

etOH: 2

0% rH

HLB 15: 2

8% et

OH: 40%

rH

HLB 4.3: 16%

etOH: 6

0% rH

HLB 15: 1

6% et

OH: 60%

rH

HLB 15: 1

6% et

OH: 20%

rH

HLB 9.65: 28%

etOH: 6

0% rH

HLB 4.3: 28%

etOH: 4

0% rH

HLB 4.3: 4%

etOH: 4

0% rH

HLB 9.65: 4%

etOH: 6

0% rH

HLB 9.65: 28%

etOH: 2

0% rH

HLB 9.65: 4%

etOH: 2

0% rH

Elastic stiffness (N.mm)

10

20

30

40

50

60

70

80

90

100Force (N)

Tensile Force (N)

Distance (mm)

Work of compression (N.mm)

2

2

4

6

8

10

12

14

16

Force (N)

Distance (mm)

0

2

4

6

8

10

12

14

16

18

20

22

-2-4-6

Copyright © Tillotts Pharma AG 2012 www.tillotts.com

Focus on TechnologyWithin this section we aim to profile a technology area related to our business.

In this section we share recent in-house data highlighting the use of Texture Analysis Methods for assessing the impact of lipid based formulations containing critical levels of co-solvents on mechanical properties like elasticity, brittleness and softness of hard shell capsules. In the following the results obtained with two different texture analysis methods have been compared.

Lipid formulations filled into two piece hard shell capsules have gained increasing interest in last two decades due to its proven effect improving the oral bioavailability of compounds with suboptimal physicochemical properties [1]. Hydrophilic co-solvents have been broadly used in Type IV lipid-based drug delivery systems [2]. However, depending on their amount in the lipid formulation, co-solvents might lead to compatibility issues like softness or brittleness of the capsule shell, deformation of the capsules or inducing leakage of the formulations [3]. Therefore, an understanding of critical level of co-solvents influencing the shell integrity of hard capsules is crucial during early pharmaceutical development.

In this investigation model lipid-based formulations containing different levels of co-solvents were used. The effect of three different factors on the mechanical properties of hard shell capsules was investigated, namely the Hydrophilic-Lipophilic Balance (HLB) of the lipidic component, the amount (%) of ethanol as hydrophilic co-solvent, and the relative humidity (% rH) during 2 weeks of storage of the filled capsules. Texture analysis (TA.TXPlus Texture Analyser from Stable Micro Systems®) was used to monitor changes of liquid-filled hard shell capsules. Two texture analysis methodologies (modes) were used, the compression and the force-in tension modes. While the compression mode has been traditionally used for assessing properties of hard shell capsules [4], limited information is available on the force-in-tension mode [3].

The effect of the different factors on the integrity of the capsule shell was investigated using gelatine and hydroxypropylmethylcellulose (HPMC) hard shell capsules. Rather challenging formulations were selected in order to study the mechanical limits of the capsules. Hard gelatine capsules were found to better tolerate the challenging formulations, and therefore were selected for further texture analysis investigations. Table 1 summarizes the correlations between the responses obtained from the two texture analysis methods.

Table 1Correlations between responses obtained by two different texture analysis methods

Figure 5Mean of work of compression responses of the different capsules on storage

Figure 1Compression mode

Figure 2Compression – relaxation diagram

Conclusions

A successful hand-to-hand comparison and a good correlation between the responses from two texture analysis methods was obtained

Texture analysis in compression mode was found to be a suitable tool to assess mechanical changes of hard gelatine capsules

Compression mode was of practical advantage, because liquid-filled capsules can be directly investigated without any previous handling (manipulations)

The laborious emptying and cleaning of capsules needed for force-in-tension mode is not required

Compensating effects of factors like co-solvent level, formulation polarity and environmental humidity can lead to capsules with little mechanical change by texture analysis. Such effects must be considered and corroborated by other techniques (i.e. microscopy) to assure an adequate assessment of the mechanical properties of liquid-filled capsule drug products

References [1] Jannin V., Musakhanian J., Marchaud D. (2008). Approaches for the development of solid and semi-solid lipid-based formulations. Adv Drug Deliv Rev. 17: 734-46.

[2] Mohsin K. (2012). Design of lipid-based formulations for oral administration of poorly water-soluble drug fenofibrate: effects of digestion. AAPS PharmSciTech. 13:637-46.

[3] Mei X. et al. (2006). Use of texture analysis to study hydrophilic solvent effects on mechanical properties of hard gelatine capsules. Int. J. Pharm. 324: 128-135.i

[4] Kuentz M. and Röthlisberger D. (2002). Determination of the optimal amount of water in liquid-fill masses for hard gelatine capsules by means of texture analysis and experimental design. Int. J. Pharm. 236: 145-152.

Figure 1 represents the texture analysis devise used for working in compression mode. A cylindrical plate sensor was used to compress the entire capsules up to a displacement of 1.3 mm (strain range) at a the controlled speed of 0.5 mm/s. Figure 2 shows the responses obtained, namely compression force (N) and the work of compression (N.mm) calculated from the compression – relaxation steps.

For the force-in-tension mode, capsule bodies were mounted on two short rods separated by a distance of 1 mm. One rod was fixed and the other moves upwards with a speed of 0.5 mm/s until bodies were pulled apart (Figure 3). Figure 4 shows a typical force–displacement diagram obtained by force-in-tension mode. The force applied at rupture point or tensile force (N) and the slope of the linear section of the curve or elastic stiffness (N.mm-¹) were recorded.

Figure 3Force-in-tension mode

Figure 4Force–displacement diagram

The work and force of compression obtained from the compression mode did perfectly correlate each other, and also a good correlation of these responses was obtained with the tensile force from the force-in-tension mode. Only the elastic stiffness was found not to correlate with the force and the work of compression (p-value>0.05), the latter being non-destructive to the capsules. Therefore, the focus was set to the compression mode, specifically to work of compression as main response. The effect of three parameters and their possible interactions were investigated. As shown by figure 5 significant differences on the work of compression responses were found among the groups (p < 0.05). As expected, some of the rather challenging formulations clearly caused significant mechanical changes on the capsule shell. However, other capsules were found in the range of control units. Probably in later case, the co-solvent effect on shell brittleness was balanced to some extent by a compensatory effect of the storage humidity that rather softened capsules.

RESPONSES Work of compression Tensile force Elastic stiffness

Force of compression 0.0007 0.011

0.0172

0.3325

0.4271

0.0148

Work of compression

Tensile force

Wor

k of

com

pres

sion

(N.m

m)

contro

l

contro

l 20%

contro

l 40%

contro

l 60%

HLB 9.65: 16%

etOH: 4

0% rH

HLB 15: 4

% et

OH: 40%

rH

HLB 4.3: 16%

etOH: 2

0% rH

HLB 15: 2

8% et

OH: 40%

rH

HLB 4.3: 16%

etOH: 6

0% rH

HLB 15: 1

6% et

OH: 60%

rH

HLB 15: 1

6% et

OH: 20%

rH

HLB 9.65: 28%

etOH: 6

0% rH

HLB 4.3: 28%

etOH: 4

0% rH

HLB 4.3: 4%

etOH: 4

0% rH

HLB 9.65: 4%

etOH: 6

0% rH

HLB 9.65: 28%

etOH: 2

0% rH

HLB 9.65: 4%

etOH: 2

0% rH

Elastic stiffness (N.mm)

10

20

30

40

50

60

70

80

90

100Force (N)

Tensile Force (N)

Distance (mm)

Work of compression (N.mm)

2

2

4

6

8

10

12

14

16

Force (N)

Distance (mm)

0

2

4

6

8

10

12

14

16

18

20

22

-2-4-6

14 - 16 May 2013

BioTrinityNewbury, UK For more information please visit: http://www.biotrinity.com

22 - 24 October 2013 CPhI/ICSE Frankfurt, Germany

For more information please visit:http://www.cphi.com/event-calendar

www.tillotts.com

Welcome to the last 2012 edition of our quarterly Newsletter. We are very delighted about the positive feedback regarding our Newsletter during the past period. Within this edition we introduce Solid Form Solutions Ltd., a contract research organisation, which is working with Tillotts Services within a co-promotion agreement. Our technology article profiles the use of Texture Analysis Methods for assessing the impact of lipid based formulations. Also we report about our forthcoming event attendances as well as our staff interview.

Since January 2012 Tillotts Pharma AG has entered a collaboration with Solid Form Solutions (SFS) which is very successful (we refer to our article in the Newsletter 4) and we will continue this relationship. In this issue we are pleased to publish an article of Dr. Stephen Watt (CEO). Many thanks to you, Stephen and your team for this efficient cooperation.

[Dr. Stephen Watt, CEO, Solid Form Solutions Ltd.] Solid Form Solutions Ltd is a contract research organisation (CRO) located just outside Edinburgh in Scotland. The company provides the pharmaceutical industry with salt, polymorph and co-crystal screening services as well as scale-up crystallisation programs. The company also has a very high level of expertise in controlling particle size

and morphology during the crystallization process. The company’s unique selling point is that they have been able to bridge the gaps very successfully between the bench and manufacturing plant.

Issue 7

NEWSLETTER

Acknowledgements: Design by David Anthony, AK Design (Scotland) Ltd.

For more information, please contact us at:

Q: So Hansueli please tell us a little about yourself?

A: I have the big advantage to live with my family here in Ziefen. So my way to work by bicycle is very short. We are living in an old house with a big garden and we have a dog, some chicken and a cock (for the wake up cark). Two of our three children are still living at home as they are continuing their study. By the way, people who can’t pronounce my typical Swiss name just call me Hans. I like driving slow old tractors and also fast new motorbikes.

Q: When did you join Tillotts?

A: In January 2002 I started at Tillotts as production manager.

Q: What is your role within Tillotts?

A: Today I am the Head of Tillotts Services and this includes the departments Contract Services & Business Development, Logistics, Production & Packaging, Engineering and Quality Control. Together with my team, which is the best, we produce several products for our different customers in the necessary quality according the GMP regulations.

Q: What was the biggest challenge for you at Tillotts?

A: In 2009 when the company was for sale, we had a big uncertainty internally and also towards our different customers about the future business. We were able to keep our production volume and our motivation for the daily work. We created and implemented a new business plan for Tillotts Services.

Q: What will be your next big challenge at Tillotts?

A: After my 60th birthday I plan to reduce my working time to 80% and I have to find and train my successor.

Q: Of which project are you most proud?

A: I am very happy to be part of this GMP facility in Switzerland and to produce a set of different products for several big pharmaceutical companies outside Switzerland. Every day, week, month, year we have new tasks and new projects and we are able to complete them in time and in good quality.

Q: Why is Tillotts the best company for you?

A: The Ziefen factory is a small unit and everyone knows all procedures. For all challenges we find the right solution. The whole team is highly motivated to do a good job and to serve our customers with the best service. The equipment is well maintained and we can invest in new machinery. I am very satisfied working in this international team which is part of Tillotts Pharma AG with its headquarters in Rheinfelden and our Japanese parent company, Zeria Pharmaceutical Co. Ltd. in Tokyo.

In this edition Miriam Adler interviews Hansueli Schaub, Head of Tillotts Services

ww

w.tillotts.com T: +41 61 935 28 28

F: +41 61 935 28 29E: services@tillotts.com

Tillotts Pharma AGTillotts ServicesHauptstrasse 274417 ZiefenSwitzerland

Tillotts Services will be represented at the following events during 2013. We would be delighted to meet with you.

Let’s Have Coffee..

The successful collaboration between Tillotts Pharma AG and Solid Form Solutions Ltd. continues

Follow us on LinkedIn:Please join our LinkedIn Group “Tillotts Services” on LinkedIn. We will inform you about several forthcoming events as well as the latest news within Tillotts Services.

See us on YouTube:If you are interested in the Liquid Fill Encapsulation Technology as well as in the manufacturing process of Tillotts Services you have now the opportunity to follow us on YouTube.

picture source: Solid Form Solutions Ltd.

As well as small molecules, SFS have worked on many peptide crystallisation projects that have simplified the purification of these complex materials. Furthermore, SFS has demonstrated the presence of polymorphism in these compounds. The company leads in this area and has supported a number of very successful scale-up campaigns that have seen their clients move rapidly through development. More information can be found at: http://www.youtube.com/watch?v=jKLf_EK0j-w

Solid Form Solutions is also on the “Road to GMP” and by early 2013 expects to have been inspected by the MHRA, allowing the company to release material as part of their client’s GMP campaigns, which will serve to strengthen their combined offering with Tillotts.

SFS see their partnership with Tillotts Pharma as a unique and powerful tool for drug development, providing clients with not just an excellent chemical development program; but, access to the best formulation technologies and strategies in the business.

CEO of SFS, Dr Stephen Watt, says “our partnership with Tillotts Pharma has been an excellent success and we are looking forward to introducing new services that will facilitate and compliment the services of Tillotts further, making drug development even faster and more economical for clients”.