1. business and industrial
2. agriculture and forestry
3. crops and seed

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2011
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The XXII Symposium of the
Finnish Society of Physical Pharmacy
DEVELOPMENT AND CHARACTERIZATION
OF SOLID DOSAGE FORMS
February 10th, 2011
Hotel Savonia – Kuopio, Finland
The XXII Symposium of the
Finnish Society of Physical Pharmacy
DEVELOPMENT AND CHARACTERIZATION
OF SOLID DOSAGE FORMS
Symposium program:
9:00
Registration and coffee
9:45
Opening of the Symposium
Chairman of the Society, Juha Mönkäre
10:00
Development of a lubricant coated binder
Reinhard Vollmer, JRS Pharma, Germany
11:00
New insights for tablet compression
Satu Lakio, University of Helsinki, Finland
11:30
Solid dosage form manufacture using printing technology
Niklas Sandler, Åbo Akademi University, Finland
12:00
Introduction to Promis Centre
12:10
Lunch
13:00
Posters and exhibition
14:00
Engineering crystals with desired mechanical behaviour
Ronald Roberts, AstraZeneca, United Kingdom
15:00
Coffee, posters and exhibition
15:30
Non-destructive evaluation of tablets using ultrasound
transmission measurements
Simo-Pekka Simonaho, University of Eastern Finland
16:00
Development and characterization of amorphous API-API
mixtures
Jaakko Aaltonen, University of Helsinki
16:30
Closing words of the Symposium
18:00
Symposium Dinner
ISSN:
1236–4002
1458–5820 (pdf )
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The society acknowledges the support from its partners:
d Controls Company.
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dental or consequential damages in
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er, Morphologi, r, Rosand, SyNIRgi,
truments Ltd.
Experimental data
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Data collected using Ag radiation (λ = 0.5594 Å)
For more information, please contact:
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Table of contents
Päätoimittajan palsta................................................................................................................................................
8
Greetings from the chair..........................................................................................................................................
9
Lecture abstracts........................................................................................................................................................
11
Development of a lubricant coated binder.................................................................................................................................
12
New insights for tablet compression.............................................................................................................................................
14
Solid dosage form manufacture using printing technology.................................................................................................
16
Engineering crystals with desired mechanical behavior........................................................................................................
18
Development and characterization of amorphous API-API mixtures................................................................................
19
Non-destructive evaluation of tablets using ultrasound transmission measurement technique..........................
20
Poster abstracts............................................................................................................................................................. 23
Theophylline-nicotinamide cocrystal formation in physical mixture during storage.................................................
24
Particle drug coating as an efficient approach to improve uniformity of content of single-dose preparations 24
6
Homogeneity testing of continuously manufactured tablets..............................................................................................
25
Designing injectable porous silicon formulations....................................................................................................................
25
Determination of water content in freeze dried samples using NIR spectroscopy......................................................
26
The search of stabilizing excipients for amorphous drugs using computationally determined Flory-Huggins
interaction parameter.........................................................................................................................................................................
27
Stealth artemether formulation for effective treatment of malaria....................................................................................
27
Novel Calorimetric Flow-Through Method for Determination of Dissolution Enthalpy.............................................
28
Micro-computed tomography in characterization of surface erosion of photocrosslinked poly(ester
anhydride)...............................................................................................................................................................................................
29
PhD and MSc theses 2010.........................................................................................................................................
31
Chemometric methods in pharmaceutical tablet development and manufacturing unit operations................. 32
Interplay of Passive and Active Drug Disposition in in vitro Models of Drug Absorption and Distribution
32
In vitro Model of Retinal Pigment Epithelium for Use in Drug Delivery Studies.............................................................
32
Granulation in Miniaturised Fluid Bed Using Electrostatic Atomisation...........................................................................
33
Towards real-time understanding of processes in pharmaceutical powder technology...........................................
33
Mechanistic Studies of Drug Dissolution Testing : Implications of solid phase properties and in vivo
prognostic media..................................................................................................................................................................................
34
Miniaturization of Drug Solubility and Dissolution Testings.................................................................................................
34
Ultrasound-assisted surface engineering of pharmaceutical powders............................................................................
35
List of MSc theses from the participating Universities............................................................................................................
36
Pharmaceutical Solid State Research Cluster — kiinteiden lääkemuotojen kansainvälinen
tutkimusverkosto.......................................................................................................................................................
38
Farmasian opetus ja tutkimus Tarton yliopistossa.........................................................................................
40
List of Participants......................................................................................................................................................
43
Fysikaalisen farmasian 23. symposium — The 23rd Symposium of Physical Pharmacy..................
44
Päätoimittaja:
Henrik Ehlers, Helsingin yliopisto
Taitto:
Ermei Mäkilä, Turun yliopisto
Julkaisija
Fysikaalisen farmasian yhdistys ry.
polymorfi@fysikaalinenfarmasia.fi
www.fysikaalinenfarmasia.fi
7
Yhdistys tiedottaa
Päätoimittajan palsta
Hyvät lukijat,
Polymorfi on tänä vuonna erinäköinen kuin aikaisempina vuosina. Tämän voisi katsoa olevan
osa Fysikaalisen farmasian yhdistyksen visuaalisen ilmeen uusimista, joka alkoi Internet-kotisivujen
uusimisesta viime vuoden symposiumin alla.
Polymorfin visuaalisesta ilmeestä voimme kiittää Ermei Mäkilää. Hän on ihailtavalla innostuksella raikastanut sekä symposiummainosten että nyt myös Polymorfin ilmettä. Ermeille suuri kiitos
päätoimittajan työn helpottamisesta!
Tänä vuonna lehdessä on kansainvälinen teema. Lehdessä on esitelty artikkelien muodossa sekä
Pharmaceutical Solid State Research Cluster –tutkimusverkosto että Tarton yliopiston fysikaalisen
farmasian tutkimusta. Toivottavasti saamme esitellyt kansainväliset kontaktit hyödynnettyä myös Fysikaalisen farmasian yhdistyksen symposiumin järjestelytyössä, jotta yhdistys jatkossa saisi lisää kansainvälisiä symposiumvieraita.
Polymorfissa on myös julkaistu ensi vuoden symposiumin ensimmäinen mainos. Tämä johtuu
symposiumin järjestelyrutiinien muutoksesta, josta voit lukea lisää lehden loppupuolella.
Toivon lukijoille aktiivista osallistumista symposiumiin ja mukavia lukuhetkiä!
Terveisin,
Henrik Ehlers
Päätoimittaja
The Finnish Society of Physical Pharmacy
Members of the Board 2010–2011 and
the Organizing Committee of the XXII Symposium
Juha Mönkäre, chair
School of Pharmacy
University of Eastern Finland
Ira Soppela, vice chair
Division of Pharmaceutical Technology
University of Helsinki
Tuomas Ervasti, secretary
School of Pharmacy
University of Eastern Finland
Ermei Mäkilä, treasurer
Department of Physics and Astronomy
University of Turku
Henrik Ehlers, editor-in-chief
Division of Pharmaceutical Technology
University of Helsinki
Petteri Heljo
Division of Pharmaceutical Technology
University of Helsinki
Lotta Bergman
Department of Physical Chemistry
Åbo Akademi University
Marju Väkiparta
Orion Pharma
Laura Leimu
Orion Pharma
Joakim Riikonen
8
Department of Applied Physics
University of Eastern Finland
Greetings from the chair
The past year has meant one fundamental change for the Society as annual symposia have been
started to plan in two-year cycles. Hence, in 2010, the Committee of the Society has been working
not only to organize the 22nd Annual Symposium in Kuopio but has already started to plan the 23rd
Annual Symposium in Helsinki, February 2012. Hopefully, this change facilitates particularly programme planning as more time is available for searching for high-quality speakers. Earlier, it has often
been busy schedule to organise everything from scratch in less than year, starting from the selection of
the symposium theme until the finalization of practical arrangements. In addition, the current Committee wishes that this will bring more continuity for the symposium planning and that it eases the
workload of the future Committees.
The 22nd Annual Symposium, organized in Kuopio, February 10, 2011 discusses “Development
and characterization of solid dosage forms”. It features two international speakers, Reinhard Vollmer
from JRS Pharma and Ronald Roberts from AstraZeneca, representing industrial views on the topic
while domestic speakers are coming from academia. This topic was based on the feedback from the
membership and because these topics have not been in the symposium programme lately. In addition,
solid dosage forms are always attracting immense attention as they remain as the most popular dosage
form.
The next, 23rd Annual Symposium will organised in Helsinki, February 9, 2012 and the practical
arrangements have been already started. However, the theme of this symposium is still under consideration and thus any suggestions for interesting topics and potential speakers for those topics are
welcomed.
Other advancements of the past year were the support for ESTAC conferece bid and applying
membership of Finnish Federation of Learned Societies (Tieteellisten Seurain Valtuuskunta). The
Society supported the bid of Division of Thermal Analysis and Calorimetry in Finland for 11th European Symposium on Thermal Analysis and Calorimetry to be organized in Finland, 2014. Tentatively,
it has been planned that this conference would include a session for pharmaceutical analysis and
characterization and the Society could involved in the planning. In addition, the Society applied membership of Finnish Federation of Learned Societies, representing over 250 Finnish scientific societies.
The membership could help, for example, getting funding for symposium organizations, as happened
already in 2011. The decision of the application will be made in March 2011.
Finally, I would like to thank and all Committee members for their invaluable contribution over
the past 12 months planning and organizing symposia in Kuopio and Helsinki. In addition, I want to
acknowledge speakers, sponsors and participants of the 22nd Annual symposium for their effort and
involvement in the symposium, the annual main event of the Finnish Society of Physical Pharmacy.
Juha Mönkäre
The Finnish Society of Physical Pharmacy (chair)
9
Lecture abstracts
11
Plenary Lecture
Development of a lubricant coated binder
R. Vollmer and E. Stovanov
Technical Competence Center, JRS Pharma, Holzmühle 1, 73494 Rosenberg, Germany
Nowadays the pharmaceutical industry is under
increased pressure to lower the drug costs, accelerate
the time to the market and improve the product performance.
Pharmaceutical scientists developing a direct compression formulation usually need several conventional excipients coming from different functional groups
(fillers, binders, superdisintegrants and lubricants) to
obtain reliable powder and tablet parameters. To find
the right balance between excipients used for the formulation is a time consuming, expensive and difficult
technological process.
In the JRS Pharma laboratories a new high functionality binder was developed, which combines binding, disintegration and lubrication properties.
These 4 components were co-processed: microcrystalline cellulose, silicon dioxide, sodium starch
glycolate and sodium stearyl fumarate. After the coprocessing step, the shape of the resulting particles
differs significantly from the single substances (Figure
1). The new co-processed material was named “All-
rounder”, because it combines all properties of the
main excipients for tablet pressing.
The shape of the new All-rounder particles leads to
better flowability and allows higher speed of the tablet
press. Moreover, tablet hardness is higher compared
with the physical mixture (Figure 3) and the ejection
forces are lower.
The lubricant is fixed to the All-rounder particle.
As a consequence, during mixing process the lubricant can’t move separately, as a result no fatty layer is
formed around the ingredients, which in classical formulations decreases the tablet hardness. The mixing
times with the All-rounder can be much longer than
with magnesium stearate (Figure 2). Longer blending
gives better content uniformity especially in low dosage formulations.
As can be seen in Figure 3, the tablet hardness with
the All-rounder is higher compared with the physical
mixture of the single components.
Because of the excellent flowability of the Allrounder, trials were conducted on a high speed rotary
Figure 1: Left: physical mixture of the components; Right: co-processed material.
12
3.50
100
3.00
Tensile Strength [MPa]
Tablet Hardness in %
95
90
with Mg-Stearate
2.50
2.00
1.50
1.00
85
0.50
0.00
80
0
10
20
30
40
50
60
Blending Time [min]
Figure 2: Using the All-rounder (solid line), blending time
has no influence on the tablet hardness.
0
5
10
15
20
25
30
Compression Force [kN]
Figure 3: Tablet hardness of a paracetamol tablet: 60 %
paracetamol and 40 % All-rounder (solid line) vs. 60 %
paracetamol and 40 % physical mixture (dashed line)
press. For these trials we used the Fette 2090i. The aim
of the study was to find out at what speed a content
uniformity of 2.5 % was reached.
Even at a speed of 300 000 tablets / hour the content uniformity of the All-rounder version was below
2.5 % rel. std. dev. With the physical mixture the 2.5 %
were reached this content uniformity at 70 000 tablets
/ hour.
Table 1: Content uniformity of paracetamol tablets expressed
as the relative standard deviation (%)
Tablets / h
All-rounder
Physical mixture
100 000
1,4 %
4,8 %
200 000
2,0 %
7.3 %
300 000
2,4 %
–
The increase of the speed of the tablet press leads
to shorter production times, which is a significant save
in production costs.
Due to the success of these trials, we have commercially launched the All-rounder in the market under
the name PROSOLV® EASYtab.
About the presenter
Dr. Reinhard Vollmer obtained a degree
in food chemistry and biochemistry at
University of Karlsruhe. After working
as a Research Scientist in the Department of Biochemistry at University of
Heidelberg, he received a PhD from
that University.
In 1982 Dr. Vollmer started in the Galenic Department at Boehringer Ingelheim. He worked on development
and registration of ODT pharmaceuticals. Besides that he was
head of an analytical laboratory.
In 1995 Dr. Vollmer joined Penwest Pharmaceuticals Co. as a
managing director of the German Penwest sales office. From
that time his main research field was excipients, mainly for
direct compression of tablets.
After Penwest was bought by Rettenmaier & Söhne, a German excipients company, Dr. Vollmer took over the Technical
Compentence Center. The TCC laboratories are working on
tablet formulations for customers world-wide. Another topic
is search for new substances for tabletting.
13
Invited Lecture
New insights for tablet compression
Satu Lakio
Division of Pharmaceutical Technology, University of Helsinki, Finland
The importance of initial particle size in compaction processes has been known since the 1950s. Particle size and size distribution influence flowability [1,
2], tabletability [3], content uniformity [4, 5], tensile
strength of tablets [6] and tablet dissolution properties [2, 7, 8]. Particle rearrangement during compaction is affected by the particle size and size distribution
[9]. Smaller particles can enter the voids between the
larger particles, thereby inducing a closer packing arrangement during the tabletting process. The particle
size distribution of the compressed mass can change
during the tabletting process, due to the segregation
phenomenon [10]. A distinct trend has been found between the segregation tendency and weight variation
of the tablets [10, 11]. Therefore quality problems for
the final dosage form may occur due to segregation.
Segregation is more likely to occur for wide size distributions than for narrow size distributions [10].
Compression data have usually been evaluated
by studying the compression force profile for single
tablets [12-16]. Force, time and displacement curves
have usually been studied to acquire information on
the compaction properties of pharmaceutical materials. However, only few studies are available in which
all the compression data of the entire batch have been
evaluated [10].
The aim of this study was to evaluate how different
granule size distributions affect the tablet compression
process. The emphasis was on developing new analytic methods for compression data for entire batch.
In all, 18 batches of granules containing theophylline
and lactose were tabletted, using an instrumented eccentric tabletting machine. During tablet compression,
upper and lower punch forces were recorded (Fig. 2).
Regarding median particle size, five batches were chosen for closer inspection (batches 2, 5, 9, 13, 17).
The results suggested two types of undulation in
the tabletting data: 1) short-time scale variation or
tablet-to-tablet changes in force data and 2) long-time
scale undulation describing the changes occurring
throughout the tabletting process, such as segregation.
Homogenous and sufficiently small material has no
short-time scale variation, although it is possible only
in theory. However, when spherical pellets whose particle size was 200 µm were compressed, the undulation
was small (Fig. 1).
The undulation increased when the particle size
of the pellets was increased – when the pellet size
Figure 1: Effects of particle size of cellets on upper punch force during tabletting.
14
ing materials were mixed with no granulation. This
mixture showed difficulties in compression i.e. it did
not flow from the hopper onto the tabletting table. The
mixture also showed the poorest tabletting properties
(Fig. 2). For these materials, the adequate particle size
for tabletting was approximately 200 µm.
Acknowledgements
Orion Pharma is acknowledged for support. In addition Simo Siiriä, Heikki Räikkönen, Sari Airaksinen,
Tero Närvänen, Osmo Antikainen, Juha Hatara and
Jouko Yliruusi are acknowledged.
References
Figure 2: Effective compression force (Feff) for powder mixture, batch 17, batch 13, batch 9, batch 5 and batch 2.
was 700 µm, the undulation was considerably larger
(Fig. 1). In this case the undulation was derived from
the fact that the larger pellets could not fill the tabletting mould evenly, in which case there were various
amounts of pellets in the mould each time. If the mass
included several sizes of particles, as tabletted masses
usually do, the smaller particles could fit into the gaps
between the larger particles, leading to smaller undulations in the tabletting data. Variations in the mass in
the mould increased and the mould was filled differently each time. In practice, each mass induces some
short-time scale variation in the compression data.
Long-time scale undulation is defined as a waving
kind of undulation that occurs during tabletting. It can
reveal segregation of the mass in the hopper. If there
were broad particle size distributions in the mass, the
possibility of segregation would be clear. In the present study segregation was established in as simple a
way as possible, using variously sized cellets. A 50/50
mixture of cellets (200 µm and 700 µm) was compressed. Fluctuation that was typical for segregation
can be seen in Figure 1. Fluctuation in the compression force during tabletting was clearly smaller with
cellets having a smaller particle size than that observed
with cellets of a larger particle size.
The results suggested that the smaller the particle
size, the better the tabletability. However, there has
assumed to be a minimum particle size for adequate
flowability. To determine the smallest acceptable particle size, an additional study was preformed. The start-
[1] Fan et al., 2005. Am. Pharm. Rev., 8 (2), 73-78.
[2] Deanne and Etzler, 2007. Am. Pharm. Rev, 10(3), 132-136.
[3] Sun and Himmelspach, 2006. J. Pharm. Sci. 95(1), 200–206.
[4] Yalkowsky and Bolton, 1990. Pharm. Res. 7(9), 962-966.
[5] Rohrs et al., 2006. J. Pharm. Sci. 95(5):1049-1059.
[6] Olsson and Nyström, 2001. Pharm. Res. 18(2), 203-210.
[7] Carless and Sheak, 1975. J. Pharm. Pharmacol. 28, 17-22.
[8] Jillavenkatesa et al., 2002. Am. Pharm. Rev. 5, 98– 105.
[9] Patel et al., 2006. Crit. Rev. Ther. Drug Carrier Syst., 23(1),
1-65.
[10] Virtanen et al., 2009. J. Pharm. Sci., 99(4), 2061-2069.
[11] Antikainen et al., 2006. AAPS Journal, 8 (S2).
[12] Marshall, 1989. Drug Dev. Ind. Pharm., 15(13), 2153-2176.
[13] Schmidt and Vogel, 1994. Drug Dev. Ind. Pharm., 20(5), 921934.
[14] Yliruusi et al., 1997. Drug Dev. Ind. Pharm., 23(1), 63-68.
[15] Nicklasson and Alderborn, 2000. Pharm. Res. 17(8), 949-954.
[16] Patel et al., 2007. Pharm. Res. 24(1), 111-124.
About the presenter
Satu Lakio finished her PhD in 2010
at the University of Helsinki in Finland where she specialized in pharmaceutical technology. The title of
her thesis was ‘Towards real-time
understanding of processes in pharmaceutical powders technology’.
During her five year PhD project she
worked in industrial driven project
involved with Process Analytical
Technologies for three years. Recently she has worked as a
senior lecturer and researcher at the Division of Pharmaceutical Technology at University of Helsinki.
She has a background in solid state chemical and physical
characterization especially in powder technology processes.
In addition she has been working with many of the spectroscopic and other analytical methods.
15
Invited Lecture
Solid dosage form manufacture using printing
technology
Niklas Sandler
Department of Biosciences, Åbo Akademi University, Finland
Medicines are often oral solid dosage forms made
into tablets or capsules and there is little room for individualized doses. The API and additives are processed
through multiple production phases including complex powder handling steps. Inkjet printing technologies have emerged over the last decades in pharmaceutical and biological applications and offer solutions for
controlling material and product characteristics with
high precision. The talk will introduce the concept of
conventional inkjet printing technology to produce
printable pharmaceutical dosage forms on porous substrates. Data is shown to demonstrate inkjet printing
of active pharmaceutical ingredients into paper substrates and how the model drug substances (paracetamol, theophylline and caffeine) are penetrating the
porous substrates used. The approach enables controlling not only the deposition but also the crystallization
of the drug substances. We anticipate inkjet printing
has immense potential in making sophisticated drugdelivery systems by use of porous substrates in the
future. For example, it may offer new perspectives to
create solutions to fabricate on-demand individualized
medicines for patients.
References
Calvert, P., 2001. Chem. Mater. 13 (10), 3299–3305
de Gans, B-J., Duinevald, P.C., Schubert, U.S., 2004. Adv. Mat. 16:3
203-213
Forrest, S.R., 2004. Nature 428, 911-918
Sandler, N., Määttänen, A., Ihalainen, P., Kronberg, L., Meierjohann, A., Viitala, T., Peltonen, J., 2011. J. Pharm. Sci. In press
About the presenter
Niklas Sandler received his PhD in pharmaceutical technology
from the University of Helsinki in 2003 with the thesis entitled
“New perspectives for visual characterization of pharmaceutical
solids”. He was a lecturer at the Pharmaceutical Technology
Division between 2003-2005 and in 2005-2006 he took up a
postdoctoral position at the University of Otago, New Zealand, focusing on research regarding various solid-state characterization aspects of pharmaceutical materials.
He became an adjunct professor in Pharmaceutical Technology at the University of Helsinki in 2007. Between 2006
and 2008 he had a senior researcher position at AstraZeneca
Pharmaceutical and Analytical R&D in the UK. Between September 2008 and July 2009 he was an acting professor in Industrial Pharmacy at the University of Helsinki. He has been
professor in Pharmaceutics at Åbo Akademi University, Turku,
Finland, since August 2009.
Figure 1: Optical micrographs of inkjet printed paracetamol on a) PET, b) xerox paper, c) coated paper. It can be seen that
the drug substance (DS) crystallises on the PET film while the DS penetrates into the porous paper substrates. Image size
500 x 500 microns.
16
Plenary Lecture
Engineering crystals with desired mechanical
behavior
Ronald J. Roberts
AstraZeneca Ltd., Macclesfield, United Kingdom
The successful development and commercialisation of any drug requires adequate manufacturability,
stability and bioavailability, invariably organic compounds with the desired biological activity don’t exhibit adequate physical properties that meet all requirements. Most lack adequate aqueous solubility and in
vivo dissolution rate, some show high hygroscopicity,
others exhibit poor compaction properties. The main
persistent challenge in the development and manufacturing of drug products is the poor mechanical properties which lead to challenging formulation and process
fixes. Difficulties often arise during the processes of
milling, blending and compaction because of poor
mechanical properties of the powdered drug. Crystal
engineering could be the answer to these problems because using design principles it might be possible to
modify the physical properties based on some of the
understanding gained in evaluating the effect of crystal structure on proprerties. A partnership between
the synthetic organic chemist and the pharmaceutical
scientist in early development is one route to modification of the molecule and hence crystal structure by
modification of non functional groups whilst maintain
biological activity. Others include variation in polymorph, but more importantly would be the formation
of salts or co-crystals (not forgetting the importance of
hydrates) and use of these crystal formers to engineer
the desired mechanical properties.
This presentation will explore whether with current knowledge we have sufficient understanding to
be able to use crystal engineering design principles to
improve pharmaceutical developability.
About the presenter
Dr. Ron Roberts currently works at AstraZeneca Macclesfield
in Physical Sciences in Pharmaceutical Development as an
Associate Principal Scientist (Crystal and Powder Properties).
He has been with the company for 37 years involved in Pharmaceutics Research, Product Design, Solid State, Form Selection and Salt Selection.
His current interests are in Roller Compaction simulation and
modelling, Mechanical properties of API’s and Excipients and
the use of Neural Network and multidimensional visualization tools in Product Formulation.
He has published over 70 original papers covering mechanical properties of pharmaceuticals, compaction simulation,
expert systems, polymorph prediction and salt selection. He
is also the member of the board of the Academy of Pharmaceutical Scientists Great Britain (APSGB) and Leader of focus
group on Process Engineering and Product Design.
18
Invited Lecture
Development and characterization of amorphous
API-API mixtures
Jaakko Aaltonen
Division of Pharmaceutical Technology, University of Helsinki, Finland
The amorphous state is an attractive option to enhance the bioavailability of drugs whose bioavailability is rate-limited by their solubility, such as BCS class
II and IV drugs. However, besides exhibiting higher
solubility, being a high-energy state the amorphous
state has lower stability and tends to crystallize upon
storage and/or drug administration. The use of excipients with high glass transition temperatures (e.g., polymers) to stabilize amorphous API-excipient solid dispersions is a widely studied phenomenon, and also the
use of cocrystals (API + small-molecule coformer) is a
popular way to manipulate the solid state. On the contrary, the use of two small-molecule APIs to generate
a uniform solid form (cocrystal or “co-amorphous”)
has not been widely studied.
In this presentation the following topics will be discussed using case study examples:
1. Differences in the amorphous formation kinetics using either individual drugs or two drugs
simultaneously in a ball milling process;
2. The stability and stabilization mechanisms of
different two-component amorphous states;
3. In vitro performance and physico-relevant dissolution testing of a stable “co-amorphous”
system.
The example systems are indomethacin:ranitidine
HCl and naproxen:cimetidine. The methods applied
for solid-state analysis in this work include X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Raman and IR spectroscopy. The suitability as well as pros and cons of each technique are also
discussed.
References
Allesø M, Chieng N, Rehder S, Rantanen J, Rades T, Aaltonen J,
2009. J. Control. Release 136: 45-53
Chieng N, Aaltonen J, Saville DJ, Rades T, Eur. J. Pharm. Biopharm. 71: 47-54 (2009).
About the presenter
Dr Jaakko Aaltonen is currently a
University Lecturer at the University
of Helsinki, Finland. He received his
PhD from the University of Helsinki
in 2007. After PhD he has worked as
a Postdoctoral Fellow (University of
Otago, New Zealand) and Project
Manager (PROMIS Centre, University of Eastern Finland), before his
current position in which he was appointed in January 2011.
In 2007 he received the American Association of Pharmaceutical Scientists (AAPS) Award in Analysis and Pharmaceutical
Quality (APQ) for excellence in graduate research
His research interests are in solid-state pharmaceutics, namely solid form screening including the preparation, characterization and performance evaluation of various solid forms
including single and multiple-component crystalline as well
as amorphous forms of pharmaceuticals. He has experience
in process analytical technologies, mainly utilizing spectroscopic and chemometric methods.
Since 2004, a major emphasis in his research has been on the
development of dissolution testing methodologies to better
understand the performance and stability of different solidstate forms and solid formulations.
19
Invited Lecture
Non-destructive evaluation of tablets using
ultrasound transmission measurement technique
Simo-Pekka Simonaho
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Process Analytical Technology (PAT) and Quality
by Design (QbD) thinking have been the driving force
to develop real time measurement system for monitoring pharmaceutical processes. In addition, continuous
processing demands accurate and fast in-line monitoring tools. With the aid of new monitoring systems, the
process understanding that is essential in any process
control can be more profound and detailed. Ultrasound, among the other non-destructive testing methods, has been used to determine the porosity and elastic properties of pharmaceutical tablets and to detect
defects and anisotropy of compacted forms [1-5].
In this presentation, the focus is to use ultrasound
transmission measurement technique to determine
mechanical properties of tablets. First ultrasound is
used to evaluate the integrity of tablets. The purpose
is to separate defective tablets from a sample set consisting of both intact and defective tablets. As a defect
a small piece of parchment paper (thickness of 90 µm)
was enclosed inside excipient powder during compaction. Following excipient powders were used: dibasic
calcium phosphate dihydrate Emcompress® (DCP)
Premium JRS Pharma Budenheim Germany; microcrystalline cellulose Avicel® PH101 (MCC) FMC
Biopolymers Cork Ireland. Ultrasound measurement
were made first with a laboratory measurement set-up
(Fig.1 (left)) and then repeated using a tableting machine punches having ultrasound transducers inside of
them (Fig.1 (right)).
From the transmitted ultrasound signal, the speed
of sound and ultrasound attenuation was calculated.
The statistical difference between the intact and defected tablet groups was tested by Kolmogorov-Smirnov
Z-test and t-test of independent samples for normally
distributed parameters and others, respectively. Based
on the statistical tests, there was no statistical difference in speed of sound between the groups. However,
the ultrasound attenuation coefficient α was found to
have a higher value for defective tablets than the intact ones. Figure 2 shows the calculated ultrasound at-
20
tenuation coefficient for intact and defective sample of
DCP and MCC tablets.
Secondly tensile strength of tablets was evaluated
using ultrasound. For that purpose, sample sets of
cylindrical tablets with varying porosities were compressed and the speed of sound was measured using
the laboratory measurement set-up (Fig.1 (a)) with a
pair of 10 MHz ultrasound transducers. After the ultrasound measurements, the tensile strength of tablets
was determined using a destructive mechanical tester and compared to the speed of sound values. The
speed of sound was found to increase with the tensile
strength of the tablets as seen in Fig. 2.
Finally, statistical tests were performed to investigate the relationship between SOS and tensile strength.
The measured SOS values were divided into groups
and statistical differences between the groups were
tested using Mann-Whitney U test. For both DCP
and MCC tablets, all groups can be differentiated statistically from each other (p<0.05, Mann-Whitney U
test).
Developed ultrasound measurement system can be
used to evaluate the integrity of tablets and monitor
Figure 1: Measurement set-ups used in ultrasound transmission measurements. Left: contact transducer set-up and
right: implemented punches.
Figure 2: Ultrasound attenuation values as a function of frequency for (a) DCP and (b) MCC tablets. Standard deviation
is shown as error bars and lines are linear fits.
Figure 3: Calculated speed of sound (SOS) as a function of
tensile strength for tables compressed of (a) DCP and (b)
MCC. Solid lines are the linear fits and error bars show standard deviations.
changes in the tensile strength of tablets. The ultrasound attenuation was found to be sensitive for defects
and the speed of sound to the tensile strength of tablets. The ultrasound measuring system showed in this
presentation has great potential as a monitoring tool
during tablet compaction. As transducers are located
inside the press punches, and measurements are made
within a few microseconds, this system can be used in
the real time monitor tool of pharmaceutical tablets.
In addition, the signal analysis is based on relatively
simple Fast Fourier Transform calculations that can
be made in real time, using a real time data acquisition
hardware. Thus, this measurement system fulfills all
the required characteristics as a PAT device for in-line
monitoring system during the compaction of pharmaceutical tablets.
References
[1] Hakulinen, M.A., Pajander, J., Leskinen, J., Ketolainen, J., van
Veen, B., Niinimäki, K., Pirskanen, K., Poso, A., Lappalainen, R.,
2008. AAPS PharmSciTech, 9, 267-273.
[2] Akseli, I., Cetinkaya, C., 2008. Int. J. Pharm. 359, 25-34.
[3] Akseli, I., Mani, G.N., Cetinkaya, C., 2008. Int. J. Pharm., 360,
65-76.
[4] Akseli, I., Hancock, B.C., Cetinkaya, C., 2009. Int. J. Pharm.
377, 35-44.
[5] Leskinen, J.T.T., Simonaho, S.-P., Hakulinen, M., Ketolainen, J.,
2010. Int. J. Pharm. 400, 104-113.
About the presenter
Simo-Pekka Simonaho got his PhD
degree in the field of optical material inspection at University of
Joensuu 2005. After PhD studies,
he joined University of Kuopio and
was responsible for establishing an
acoustic laboratory at the Departemt of Physics. During 2006-2008
he worked in the acoustic laboratory.
In 2008, he joined the Department of Pharmacy at University
of Kuopio to lead a subproject entitled “Development of ultrasound measurement system for pharmaceutical tablets”. During
this project, an ultrasound measurement system for defect
detection for pharmaceutical tablets was developed.
Currently he is working as a project manager in the School of
Pharmacy at the University of Eastern Finland.
21
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• Microstructure analysis of tablets by CT
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Poster abstracts
23
Theophylline-nicotinamide cocrystal formation in
physical mixture during storage
Particle drug coating as an efficient approach
to improve uniformity of content of single-dose
preparations
Tuomas Ervastia, Jarkko Ketolainena and Jaakko Aaltonena,b
School of Pharmacy, Pharmaceutical Technology, Faculty of
Health Sciences, University of Eastern Finland, Kuopio Campus,
Finland
b
Present address: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Finland
a
Poster abstracts
e-mail: tuomas.ervasti@uef.fi / www.promiscentre.fi
Pharmaceutically relevant properties of active pharmaceutical ingredients such as chemical and physical stability
can be enhanced by cocrystal formation [1]. Theophylline
and nicotinamide are known to form cocrystals for example
via solid-state grinding [2]. However, in appropriate conditions cocrystals can also form in physical mixtures without
any mechanical activation [3].
The purpose of this work was to study whether theophylline and nicotinamide can form cocrystals spontaneously. Crystalline theophylline and nicotinamide powders
were gently mixed manually at 1:1 molar ratio and stored
at different relative humidity and temperature conditions.
The solid state of the samples was analyzed by differential
scanning calorimetry (DSC, Mettler Toledo DSC823) and
Raman spectroscopy (Kaiser Rxn1 equipped with a PhAT
probe). Three different variations of theophylline were used
as starting materials, e.g., two size fractions of theophylline
anhydrate (small: sieved through a 355 µm sieve, large: the
fraction remaining on the sieve), and monohydrate (recrystallized from water). For reference, theophylline-nicotinamide
(TP-NCT) cocrystals were prepared by solid-state grinding
with a Retsch MM400 mixer mill.
The results of this study indicate that TP-NCT cocrystals can form without any mechanical activation from physical mixtures of TP and NCT during storage. For anhydrous
samples, storage humidity was found to be a critical parameter for cocrystal formation. Increasing temperature was also
found to have an accelerating effect on the cocrystal formation. It was found that particle size had only a minor effect
on the cocrystal formation rate, probably due to the fact that
the two size fractions used were not significantly different.
In the case of monohydrate samples cocrystals were formed
almost instantly during mixing. This was probably due to
insufficient drying of freshly prepared monohydrate, and actually, the transformation was not a spontaneous solid-state
transformation, but rather a solution-mediated transformation.
References
[1] Trask A., Motherwell W., Jones W., 2006. Int. J. Pharm. 114–
123. doi:10.1016/j.ijpharm.2006.04.018
[2] Lu J., Rohani S., 2009. Org. Process. Res. Dev. 13:1269-1275.
doi:10.1021/op900047r
[3] Maheshwari C., Jayasankar A., Khan N., Amidon G., RodríguezHornedo N., 2009. Cryst. Eng. Comm. doi:10.1039/b812264d
24
Natalja Geninaa,b,c, Heikki Räikkönenb, Osmo Antikainenb,
Andrea Lanzettib,d, Jyrki Heinämäkib,c and Jouko Yliruusib
Pharmaceutical Sciences Laboratory, Department of Biosciences, FI-20500 Åbo Akademi University, Finland
b
Division of Pharmaceutical Technology, Faculty of Pharmacy,
P.O. Box 56, FI-00014 University of Helsinki, Finland
c
Department of Pharmacy, Faculty of Medicine, Nooruse 1,
50411 University of Tartu, Estonia
d
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, P.O. Box 12, IT-27100, University of Pavia, Italy
a
Purpose: To produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API) by
using an ultrasound-assisted powder coating technique.
Methods: A 4% m/V aqueous solution of riboflavin
sodium phosphate was applied onto the powdered particles
of microcrystalline cellulose, MCC (Avicel® PH-200) to produce a uniform drug layer on the particle surfaces. The tablets compressed from API-coated powder and physical mixture of powders were evaluated with respect to homogeneity
of mass and content, morphology (SEM, IFM), crushing
strength, friability and wettability.
Results: Lubricant-free tablets (n = 950) prepared from
the coated powder showed significantly improved weight and
content uniformity in comparison with the respective tablets
compressed from a physical binary powder mixture. This
was due to the fact that the coated formulation remained
uniform during the entire tabletting process, whereas the
physical mixture of the powders was subject to segregation.
In addition, the tablets compressed from the surface-coated
powder appeared to be less friable and more homogeneous
in appearance.
Conclusions: The ultrasound-assisted technique presented here is a promising tool for homogeneous drug coating of powders and for improving content uniformity of a
low-dose API in tablets. This in turn ensures the safe delivery of a potent active substance to patients.
Homogeneity testing of continuously manufactured tablets
Maiju Järvinena, Janne Paasob, Kristiina Järvinena, Mikko Juutic,
and Fernando Muzziod
School of Pharmacy, University of Eastern Finland, , Finland
VTT Technical Research Centre of Finland, Oulu, Finland
c
VTT Technical Research Centre of Finland, Kuopio, Finland
d
Dept. of Chemical and Biochemical Engineering, Rutgers University, Piscataway, USA
a
b
The pharmaceutical industry is putting more effort towards continuous processing due to its cost-effectiveness [1].
Continuous manufacturing processes save both money and
facility and equipment costs in the long run. Homogeneity
of the final product is a core attribute of quality that needs
to be controlled carefully. Aim of this study was to assess the
homogeneity of continuously manufactured tablets by ultra
violet (UV) spectroscopy (Shimadzu UV-1800). In-line measurements during process were made by multi-point near
infrared spectroscopy; these results are a topic of another
study.
Three component tablet formulation containing paracetamol (10 %), microcrystalline cellulose (89 %) and magnesium stearate (1 %) was studied. Continuous manufacturing
line consisted of loss-in-weight feeders (K-Tron and Schenck
AccuRate) and continuous blender (Gericke GCM 250), followed by a rotary tablet press (MTP-8). In first case blender
speed was 10 % of the maximum and in second case 50 %
of the maximum. Punch diameter of a tablet press was 10
mm, compression force in the first case (blue line) 8.24 kN
and the second case 7.96 kN. Tablet press rotation speed was
kept constant (35 rpm).
The results show that homogenous tablets were produced with both blender speeds, but with the higher blending speed even more homogenous tablets were obtained
(Fig. 1). When blender speed was 10 % of maximum, average concentration of paracetamol in tablets produced was
10.55 %, relative standard deviation (RSD) 5.89 %. When
blender speed was 50 % of maximum, average paracetamol
concentration was 9.92% and RSD 2.01%, respectively.
Designing injectable porous silicon formulations
Martti Kaasalainena, Ermei Mäkiläa, Joakim Riikonenb, Miia
Kovalainenc, Kristiina Järvinenc, Karl-Heinz Herzigd, VesaPekka Lehtob and Jarno Salonena, e
a
Department of Physics and Astronomy, University of Turku, FI20014 Turku, Finland
b
Department of Applied Physics, University of Eastern Finland,
FI-70211 Kuopio, Finland
c
School of Pharmacy, University of Eastern Finland, FI-70211
Kuopio, Finland
d
Institute of Biomedicine, Department of Physiology and Biocenter of Oulu, University of Oulu, FI-90014 Oulu, Finland
e
Turku University Centre for Materials and Surfaces (MatSurf),
Turku, Finland
Microparticles of mesoporous silicon (PSi) have gained
significant attention because of their potential in biomedical applications [1]. By loading the drug molecules in to the
pores, one can affect the dissolution behavior of the drug
and protect it in digestive system. One of the advantages of
porous silicon is the variety of surface treatment methods
available. Surface can be stabilized with different thermal
treatments like oxidation (TOPSi), hydrocarbonization (THCPSi) and carbonization (TCPSi). Further functionalization can be made by silylation (UnTHCPSi) or silanization
(APTES-TCPSi).
It is well known that high absolute value of zeta potential
is characteristic for agglomeration resistant suspension [2].
Recently significant role of zeta potential has noticed also in
nanoparticle-cell interaction [3]. High positive zeta potential
increases while neutral charge decreases the nanoparticles
uptake rate by the cell. These phenomena are attributed to
surface charge of cell membrane and opsonization [4].
In our study the electrophoretic mobility was measured
with ELS by Malvern Zetasizer Nano ZS. The zeta potential was calculated by using Henry’s equation and the ionic
strength was taken into account by Ohshima’s relation [5].
Zeta potential was measured in different isotonic media and
the isoelectric points were defined.
As a result we got IEPs of 2.7, 3.0, 3.7, 5.0 and 8.9 for
TOPSi, TCPSi, UnTHCPSi, THCPSi and APTES-TCPSi
nanoparticles, respectively. Also significant effect of isotonic
media was observed (Fig. 1). These results should be taken
into account when in vivo drug administration is considered.
Figure 1: Paracetamol concentration in tablets: dashed line (n=19)
refers to 10% of maximum blender speed; solid line (n=20) refers
to 50 % of maximum blender speed.
References
[1] Leuenberger H., 2001. Eur. J. Pharm. Biopharm. 52: 289–296
Figure 1: Zeta potential of PSi-nanoparticles measured in different
isotonic media.
25
Acknowledgements
This work was supported by Academy of Finland (PEPBI
consortium #118002).
fitting so that the R2 = 0,87 (blue line). First model can be
applied for fast moisture determination of the freeze-dried
products containing water < 1 % w/v with off-line and inline NIR spectroscopy.
References
[1] J. Salonen et al., J. Pharm. Sci., 97 (2008) 632–653.
[2] R. J. Hunter, Foundations of Colloid Science, Oxford University
Press, Oxford, 2001.
[3] A. E. Nel et al., Nat. Mater., 8 (2009) 543–557.
[4] C. Wilhelm et al., Biomaterials, 24 (2003) 1001–1011.
[5] A. V. Delgado et al., J. Colloid Interf. Sci., 309 (2007) 194–224.
Determination of water content in freeze dried
samples using NIR spectroscopy
Ari Kauppinena, Maunu Toiviainenb, Jaakko Aaltonenc, Ossi
Korhonena, Kristiina Järvinena and Jarkko Ketolainena
a
School of Pharmacy, Faculty of Health Sciences, University of
Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
b
Optical Measurement Technologies, VTT Technical Research
Centre of Finland, P.O. Box 1199, FI-70211 Kuopio, Finland
c
Division of Pharmaceutical Technology, Faculty of Pharmacy,
University of Helsinki, P.O. Box 56, FI-00014 Helsinki, Finland
Poster abstracts
ari.kauppinen@uef.fi / www.promiscentre.fi
In the light of the PAT initiative a more thorough understanding of process and product conditions is needed.
Spectroscopic techniques, such as near-infrared (NIR) spectroscopy, are ideal for the fast assessment of critical quality
attributes of freeze dried samples [1]. The residual moisture
content of freeze dried product was the critical quality attribute analyzed in this study. The residual moisture content
in freeze-dried products is typically very low (< 1% w/v) [2]
and has a significant effect on product stability [3].
In this study we constructed a calibration model between
NIR spectra and reference moisture values. 10 % w/v sucrose solution was used as a model excipient. Sample vials
were freeze dried using LyoStar II freeze dryer. Samples
were extracted from the freeze dryer at fixed intervals during
the process using sample extractor door. Extracted samples
were measured through the side of the vial using a NIR
spectrometer (VTT). Each analyzed spectrum was the average of 3000 spectra collected with the integration time 7,5
ms at the frame rate 100 Hz. Reference moisture values were
measured using a Karl Fischer titrator (Mettler DL 135).
As can be seen from figure 1A, the intensity of the water
band in the region about 1950 nm is clearly varied between
samples containing different amount of water. Two linear
calibration models were constructed between the water band
area (1900-2000 nm) and the reference moisture value as it is
presented in Figure 1B. Water band area correlates well with
reference moisture percentages below 1 % w/v (green line)
so that R2 = 0,98. Wet samples (> 1 % w/v) distort linear
26
Figure 1: A) NIR spectra of freeze-dried samples with varying
water content. B) Linear calibration models between baseline-corrected NIR spectra and reference moisture values corrected NIR
spectra and reference moisture values.
References
[1] Grohganz H., Gildemyn D., Skibsted E., Flink J.M. and Rantanen J., 2010. Anal. Chim. Acta 676: 34-40
[2] Pikal MJ: Freeze drying, In the book: Encyclopedia of Pharmaceutical Technology, p. 1299–1326. 2nd edition.
Eds. Swarbrick J. and Boylan J.C., Marcel Dekker, New York, USA,
2002
[3] Croyle M.A., Cheng X. and Wilson J.M., 2001. Gene. Ther. 8:
1281-1290
The search of stabilizing excipients for amorphous
drugs using computationally determined FloryHuggins interaction parameter
Katja Pajulaa, Markku Taskinena, Vesa-Pekka Lehtob, Jarkko
Ketolainena and Ossi Korhonena
School of Pharmacy, Faculty of Health Sciences, University of
Eastern Finland, P.O.Box 1627, FI-70211 Kuopio, Finland
b
Department of Physics and Mathematics, University of Eastern
Finland, P.O.Box 1627, FI-70211 Kuopio, Finland
a
katja.pajula@uef.fi / www.promiscentre.fi
Purpose: In many papers, the Flory-Huggins interaction
parameter has been shown to predict the thermodynamic
miscibility of a polymer and small molecule binary mixtures.
In this research, this approach was extended and it was evaluated whether the Flory-Huggins interaction parameter can
be extended to small molecule binary mixtures and whether
it could predict the phase stability of amorphous binary
mixtures of small molecules. This study was based on the
hypothesis that a thermodynamically miscible binary system
is stable and cannot crystallize but instead phase separation
is essential before the individual components can crystallize.
If the hypothesis is valid, with the help of modern computational methods, the Flory-Huggins interaction parameters of
large excipient sets can possibly be screened rapidly.
Methods: A group of randomly selected drug molecules
(39) were used as model compounds. Based on the DSC experiments, the drug molecules were classified into three different categories according to their crystallization tendency;
highly, moderately and non-crystallizing compounds. The
Flory-Huggins interaction parameter was systematically calculated for each drug pair. In general terms, a negative value
of the interaction parameter predicted miscibility, whereas a
positive value associated with immiscibility. The validity of
this approach was verified with the hot-stage polarized light
microscopy. Physical mixtures (50/50% on molar basis) of
both miscible and immiscible pairs of molecules were prepared, placed on the hot-stage and heated above the melting
point and subsequently cooled down to room temperature.
During the cooling segment, the crystallization of amorphous phases was detected.
Results: If both compounds in the pair belonged to the
category of highly crystallizing compound, the Flory-Huggins interaction predicted amorphous or crystalline phases
with approximately 88% (23 out of 26) confidence. If one or
both compounds of the pair belonged to moderately crystallizing or non-crystallizing compounds, the binary mixture
remained in the amorphous phase during the cooling segment regardless of the interaction parameter.
Conclusions: The Flory-Huggins interaction parameter
was found to be a reasonably good indicator for predicting
the phase stability of small molecule binary mixtures. The
method described can enable the fast screening of the potential stabilizers needed to produce a stable amorphous binary
mixture.
Stealth artemether formulation for effective
treatment of malaria
Sampada Sawanta,b, Niklas Sandlerb,Yogeeta Rajama, Natalja
Geninab and Singh K.K.a
a
C.U. Shah College of Pharmacy, S. N. D. T. Women’s university,
Mumbai 400049, India.
b
Åbo Akademi University, Department of Pharmacy and Natural
Products, Biocity, Artillerigatan 6, 20520. Turku, Finland
Introduction: Emergence of drug resistant parasite
strains indicates an urgent need for effective utilization of
existing antimalarials through the concept of novel drug
delivery system. Artemether(ARM) is a potent and rapidly
acting antimalarial agent (plasma half-life of 1 to 2 h). However, the therapeutic potential of ARM is considerably hampered due to its low oral bioavailability and it`s short plasma
half-life. ARM being an oil soluble drug, literature indicates
increased ARM bioavailability with the administration of
fatty meals. In view of this, the lipid-based delivery systems
have potential in improving bioavailability and therapeutic
efficacy of ARM. The presence of the hydrophilic layer of
PEG at the surface will impart stealth properties to the developed Lipid Nanoparticles, resulting in reduced clearance
by the MPS and thus prolonged residence time in blood.
This would lead to prolonged circulation of Artemether and
potential in improving the antimalarial efficacy. Hence objective of the present work was to design, develop surface
modified lipid nanoparticles of Antimalarial drug, Artemether and its evaluation by physical methods and pharmacodyanamic evaluation.
Experimental methods: a) Formulation development
of surface modified lipid nanoparticles: ARM Lipid nanoparticles (ALN) were prepared using melt emulsification
technique followed by high pressure homogenization. The
optimized ALN was subjected to surface modification using PEGs of different molecular weight by post insertion
method.
b) Evaluation of surface modified lipid nanoparticles:
PEGylated (PALN) and bare nanoparticles (ALN) were
characterized for physical stability, % drug content, particle
size, and polydispersity index, SEM and AFM characterizations and in vitro drug release. In vivo antimalarial activity
was carried out as per Peter’s four day suppressive test.
Results and discussion: a) Formulation development
and Evaluation of surface modified lipid nanoparticles:
ALN were bluish-white, homogeneous, stable with pH of
6.55-7and 99,5% drug content. The mean particle size was
98 nm. PALN showed increase in particle size of about 20
nm as compared to bare LN which confirmed the PEGylation (Fig: 1). The developed formulation, PALN, showed
sustained release till 24 h (79%) as compared to conventional
formulation 72% in 2 h and ALN 84% in 24 h. (Fig: 2)
b) In vivo antimalarial efficacy of surface modified lipid
nanoparticles: In vivo antimalarial efficacy on day 5 showed
that animals treated with standard ARM solution and ALN
showed percent parasitemia of 7.87 & 6.51% respectively as
27
Figure 3: In vivo antimalarial efficacy
Novel Calorimetric Flow-Through Method for
Determination of Dissolution Enthalpy
Mikko Tenhoa, Vesa-Pekka Lehtob and Jarno Salonena
Figure 1: Particle size distribution of ALN (top) & PALN (bottom)
Poster abstracts
compared to that of control group which showed highest
parasitemia (16.35%). However PALN treatment showed
lowest percent parasitemia (3.97%) as compared to all other
groups (p<0.001) showing the superiority of surface modification approach in improving the delivery of Artemether.
The antimalarial activity of PALN (74.1 & 75.7%) at 50
and 100% of therapeutic dose of ARM respectively, is higher as compared to standard ARM solution, which showed
only 43.7 and 51.9% activity at 50 and 100% dose levels respectively. Bare ALN showed much lower activity (60.2 &
62.3% at 50 &100 % dose of ARM) as compared to PALN.
Results of pharmacodynamic activity suggest that PEGylation can reduce the therapeutic dose of ARM by 50%. The
surface modification approach is advantageous in reducing
the dose related toxicity & dose related resistance issues associated with ARM and could be effective treatment strategy
of future.
a
Department of Physics and Astronomy, University of Turku, FI20014 Turku, Finland
b
Department of Physics and Mathematics, University of Eastern
Finland, FI-70211 Kuopio, Finland
A new calorimetric miniature flow-through system for
determining dissolution enthalpy as well as dissolution behavior of solids was developed [Lehto, V-P., Tenho, M.,
Hämäläinen, O-P., Salonen, J. 2010, J. Pharm. Biomed.
Anal. 53, 821-825.]. The utilization of the method only
needs very small amount of sample (<1 mg), which is a
great advantage over the traditional methods. The system
was designed to be used as an add-on cell with a 4 ml twin
heat conduction calorimeter 2277 TAM but the principle is
adoptable also for other calorimeters. The performance of
the system was tested with salts (NaCl and KCl), sucrose
and three different forms of theophylline at 25 °C and 40 °C.
Distilled water was used as the solvent. The system gave accurate results at 25 °C and also the results obtained at 40 °C
were acceptable but not as good as at 25 °C due to heat leaks.
However, all the results were in good agreement with the literature values. An example of the heat flow curves obtained
with the system is presented in the figure below. Besides determination of the dissolution enthalpy the system can be
used for studying the kinetics of dissolution. Also possible
other processes besides dissolution during the measurement
could be seen. Moreover, different sorption processes, for
example ad/absorption of ad/absorbate from the liquid to
the ad/absorbent could be studied with this novel microcalorimetric system.
Figure 2: Comparative in vitro drug release
Figure: Typical heat flow curves for dissolution of various
theophylline forms at 40 °C.
28
Micro-computed tomography in characterization
of surface erosion of photocrosslinked poly(ester
anhydride)
Juha Mönkärea, Pekka Savolainena, Risto A. Hakalab, Jari
Pajanderc, Harri Korhonenb, Jukka V. Seppäläb and Kristiina
Järvinena
a
School of Pharmacy, University of Eastern Finland, Kuopio, Finland
b
Laboratory of Polymer Technology, School of Science and Technology, Aalto University, Espoo, Finland
c
Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Copenhagen, Denmark
In ideal surface erosion, material is lost solely from the
exterior surface of the polymer matrix enabling predictable
and controlled drug delivery. Typical characterization methods of the surface erosion are the measurement of changes
of polymer molecular weight and weight of the delivery
system as a function of time, and SEM microscopy. However, these methods do not allow non-destructive analysis
of internal structure. Micro-computed tomography (microCT) can provide a detailed 3D visualization of structure in
micrometer resolution non-destructively [1]. In addition,
quantitative structural analysis can be also performed based
on micro-CT measurements. The aim of this work was to
demonstrate the applicability of micro-CT in characterization of surface erosion. Photocrosslinked poly(ester anhydride) (PEAH) was used as a model polymer since it has
been shown to be surface-eroding material [2,3]
Drug-free and drug-loaded (10 % w/w propranolol HCl,
particle size 53-149 µm) PEAH discoids (STAR1000-0M)
were placed in buffer (pH 7.4, +37˚C) in order to initiate the
erosion. Next, samples were removed from the buffer at 4-24
hours and vacuum dried at -65˚C before micro-CT imaging
with Skyscan 1172 unit (Skyscan B.V., Belgium). Finally, images were reconstructed and further analyzed and visualized
with NReconServer, CTAn and CTVol softwares (Skyscan
B.V., Belgium), respectively.
Water penetration should be limited to the matrix surface in surface erosion and any water penetration into the
polymer is seen in the form of air channels in the dried samples. In the present study, the formation of air channels was
seen only at the surface of the sample when drug-loaded and
drug-free PEAH discoids before and after buffer exposure
of 4, 12 and 24 h were evaluated. As an example, Figure
1 shows air distribution in the drug-loaded matrix at 12 h.
Practically all air shown has been entrapped as individual
bubbles during the sample preparation and air volume did
not increase during the erosion. Only at 24 h, when approximately 70% of polymer was eroded, fraction of air volume
was increased from the level of 10 to 25%V/V, and fraction
of polymer volume correspondingly decreased. In conclusion, micro-CT is a powerful method for the characterization of surface erosion.
Figure 1: Distribution of air in photocrosslinked poly(ester anhydride) matrix with 10 % w/w propranolol HCl after 12 h exposure
to the buffer. Minimal formation of air channels in the matrix is
seen which indicates that water penetration was limited on the
surface.
Acknowledgements
The financial support from the Academy of Finland (PEPBI
consortium #117906) and Graduate School of Pharmaceutical Research are acknowledged.
References
[1] Zeitler A.J. and Gladden L.F., 2009. Eur. J. Pharm. Biopharm.
71:2-22
[2] Mönkäre J. et al., 2010. J. Control. Release 146:349-355
[3] Helminen A. et al., 2003. J. Polym. Sci., Part A: Polym. Chem.
41:3788-3797
29
First Announcement
Seminar on Poor Solubility of Drugs
September 26th, 2011 – Helsinki, Finland
Organized by
The Pharmaceutical Solid State Research Cluster
For more information, please visit www.pssrc.org
Cambridge | Copenhagen | Düsseldorf | Ghent | Helsinki | Lille | Lisbon | Otago
PhD and MSc theses 2010
31
Chemometric methods in
pharmaceutical tablet development
and manufacturing unit operations
The aim of this thesis was to explore the potential benefits of chemometric methods when they are innovatively
applied in tableting manufacturing unit operations. Chemometrics is the application of statistical and mathematical methods, in particular multivariate methods, to handle
chemical or process data. It aims to explore complex relationships and extract information that is related to the system under consideration.
In this study, the molecular descriptors with multivariate
methods have been utilized as a potential tool for drug dissolution evaluation from a hydrophobic matrix tablet. In addition, multivariate and multi-way methods in conjunction
with acoustic emission data and process variables from granulation process of tableting material in fluidized bed granulation have been utilized to enhance process understanding.
In the granulation process, the best results with the models
were achieved using multi-way methods for modelling of
the process data. This was most probably due to the threeway nature of process data and batch-to-batch variation that
could not be captured using bilinear modelling. This thesis
shows the feasibility and power of multivariate data analysis
in case of analysis and evaluation of tablet development and
manufacturing unit operations.
In vitro permeation experiments with cultured cell monolayers have been applied successfully for the prediction of
the extent of intestinal absorption of compounds which
are primarily transported via the passive transcellular route.
However, simple extrapolation from the apparent in vitro
permeability to the in vivo intestinal absorption is less reliable when paracellular permeation or active transporters are
significantly involved in permeation through the epithelia. A
key characteristic of active transport is its saturability, especially in the intestine where the drug concentrations are high.
Thus, successful prediction of the active transport must account for the concentration dependency. Simple membrane
based assays as well as cell monolayer permeation experiments have been applied for studies of concentration dependent transporter function. However, the reported in vitro
determined kinetic parameters describing the transporter
saturation are inconsistent. Consequently, the extrapolation
to the in vivo setting remains challenging.
The main focus of the present study was the interplay
of active and passive drug disposition in in vitro cellular
permeation models. The effects of the experimental conditions on the apparent permeability and active transport were
examined. Furthermore, drawbacks of the data analysis approaches traditionally applied in permeation experiments
were investigated. Additionally, the pH and the protein concentration were shown to alter the observed P-glycoprotein
ATPase activation kinetics in a membrane based assay. These
results provide further insights into the dynamics of the drug
disposition kinetics in epithelial permeation as well as on
the confounding factors involved in in vitro experimental settings. Moreover, the compartmental model based analysis
applied for the in vitro permeation data seems to be a promising approach for determining transporter kinetics.
Interplay of Passive and Active Drug
Disposition in in vitro Models of
Drug Absorption and Distribution
In vitro Model of Retinal Pigment
Epithelium for Use in Drug Delivery
Studies
Aki Heikkinen
University of Eastern Finland
Eliisa Mannermaa
University of Eastern Finland
ISBN 978-952-61-0138-5
ISBN 978-952-61-0030-2
Permeation through the intestinal epithelia is a major
barrier for oral drug delivery, which is the most often utilized administration route. Therefore, there is considerable
interest in developing ways to reliably predict epithelial permeation early on in the drug discovery – development process. Consequently, several in vitro assays are utilized to gain
insight into the mechanisms involved in permeation as well
as to screen the compounds for their transport characteristics. However, the predictive value of these in vitro methods
relies to a great extent on the appropriate interpretation and
thorough understanding of the in vitro data.
The posterior location and the blood-retinal barrier
(BRB) make drug delivery in diseases affecting retina and
vitreous challenging. The outer part of BRB is composed of
retinal pigment epithelium (RPE), which restricts drug entry to the retina from the systemic circulation and from the
periocular space. In this study, filter grown ARPE-19 cells
have been characterized as a potential in vitro model of the
human RPE for use in drug delivery studies. ARPE-19 barrier properties were evaluated in different culture conditions.
The ARPE-19 model was 3-17 times more permeable than
isolated bovine RPE-choroid tissue, but the ARPE-19 model
Sanni Matero
University of Eastern Finland
PhD theses 2010
ISBN 978-952-61-0142-2
32
efficiently separated test compounds based on their lipophilicity and molecular sizes. Expression of RPE related genes,
RPE65, CRALBP, TRP1, tyrosinase and Mitf-A and OTX2
transcription factors was greatly enhanced by filter culture. It
has become evident that transporters play an important role
in pharmacokinetics. The expression of efflux proteins, pglycoprotein (P-gp), multidrug resistance associated proteins
1-6 (MRP) and breast cancer related protein (BCRP), in various RPE cell lines was studied. As with primary RPE cells,
ARPE-19 cells express MRP1, MRP4 and MRP5 efflux proteins. Efflux protein activity was evaluated in cellular uptake
studies using calcein-AM and carboxydichorofluorescein as
probe molecules, and by bi-directional permeability studies.
The studies indicate MRP1 and MRP5 activity in ARPE-19
cell line. Active transport in the ARPE-19 cell model was
qualitatively, though not quantitatively similar, with isolated
RPE-choroid tissue. Furthermore, non-viral gene transfer
was studied in the ARPE-19 cell model. Prolonged gene
expression was achieved by liposomal carriers. In conclusion, the ARPE-19 cell model can be used to screen drug
molecules with different physicochemical properties and in
gene delivery studies. The greater passive permeability may
lead to an underestimation of active transport in this model.
Several membrane transporters are expressed and active in
the ARPE-19 cell model.
Granulation in Miniaturised Fluid
Bed Using Electrostatic Atomisation
Niina Kivikero
University of Helsinki
ISBN 978-952-10-6250-6
The development of a new drug is extremely expensive
and the development process is very slow, up to 15 years.
Especially the early formulation development phase is a
challenge for the pharmaceutical industry, as the amount of
a new active pharmaceutical ingredient may only be a few
grams. A small amount of drug should be used to produce
as much data as rapidly possible.
In this thesis, a small scale fluid bed device (Multipart
Microscale Fluid bed powder Processor, MMFP) with electrostatic atomisation is used for the first time to perform
granulations. The aims of this thesis were to develop and
characterise a suitable spraying method for MMFP and to
characterise the spray. The process parameters of the electrostatic atomisation system and fluid bed granulation affecting
the granule size were studied. Also the applicability of the
set-up to early formulation studies was evaluated.
Electrostatic atomisation was found to be applicable for
spray production in a small device with a specially constructed nozzle. With particle tracking velocimetry, it was possible
to generate droplet size distributions of the produced spray.
Also a high speed imaging system provided information
about the spray. The granulation liquid flow rate affected the
granule size the most, although the atomisation voltage and
binder concentration of the granulation liquid had also an
impact on it.
MMFP provides possibilities to study granulation properties of different materials with a small sample size. Also
early formulation screening studies are possible to be conducted. The granulation process, as well as the following
analysis is fast, although a small sample size may be challenging for traditional methods.
Towards real-time understanding of
processes in pharmaceutical powder
technology
Satu Lakio
University of Helsinki
ISBN 978-952-10-6168-4
There is a need for better understanding of the processes
and new ideas to develop traditional pharmaceutical powder manufacturing procedures. Process analytical technology (PAT) has been developed to improve understanding of
the processes and establish methods to monitor and control
processes. The interest is in maintaining and even improving the whole manufacturing process and the final products
at real-time. Process understanding can be a foundation for
innovation and continuous improvement in pharmaceutical
development and manufacturing. New methods are craved
for to increase the quality and safety of the final products
faster and more efficiently than ever before. The real-time
process monitoring demands tools, which enable fast and
noninvasive measurements with sufficient accuracy. Traditional quality control methods have been laborious and time
consuming and they are performed off line i.e. the analysis has been removed from process area. Vibrational spectroscopic methods are responding this challenge and their
utilisation have increased a lot during the past few years. In
addition, other methods such as colour analysis can be utilised in noninvasive real-time process monitoring.
In this study three pharmaceutical processes were investigated: drying, mixing and tabletting. In addition tablet properties were evaluated. Real-time monitoring was performed
with NIR and Raman spectroscopies, colour analysis, particle size analysis and compression data during tabletting was
evaluated using mathematical modelling. These methods
were suitable for real-time monitoring of pharmaceutical
unit operations and increase the knowledge of the critical
parameters in the processes and the phenomena occurring
during operations. They can improve our process understanding and therefore, finally, enhance the quality of final
products.
33
Mechanistic Studies of Drug
Dissolution Testing : Implications of
solid phase properties and in vivo
prognostic media
Paula Lehto
University of Helsinki
PhD theses 2010
ISBN 978-952-10-6093-9
Drug absorption after oral administration requires that
the drug first dissolves into gastro-intestinal tract liquids. In
vivo dissolution of a drug is affected by physiological and
drug-related physicochemical factors. In the case of poorly
water-soluble drugs, in vitro dissolution testing at various
stages of drug development is especially important, since
the absorption is predominantly limited by the dissolution rate. Varying dissolution rates, possible for different
physical structures of the same chemical entity (known as
polymorphs), for example, can lead to varying degrees of
bioavailability and, potentially, result in therapeutic failure.
Traditionally, pharmaceutical dissolution testing has relied
on determination of the dissolved drug concentration from
liquid phase. This has led to poor understanding (and possible underestimation) of the connection between the change
in solid phase and dissolution behaviour. Thus, new powerful approaches are needed. To correlate in vitro dissolution
results of drug products with in vivo behaviour often requires
the use of dissolution methods reflecting conditions in the
gastro-intestinal tract. For such purpose, various physiologically based dissolution media have been proposed.
In this thesis, solid phase analysis was combined with
dissolution determinations to provide in depth understanding of the effects of solid state properties on the intrinsic dissolution rate of active pharmaceutical ingredients (API). A
new approach to dissolution testing, which involved simultaneous in situ solid phase analyses of the dissolving sample
and measurement of dissolved concentrations in the dissolution medium, were utilized to explain the implications
of solvent-mediated solid phase conversions on dissolution
processes. Simplified dissolution media were developed and
studied for the prediction of in vivo behaviour of Biopharmaceutics Classification System (BCS) class II drugs.
Quantitative solid phase analysis using Raman spectroscopy was successfully performed in situ during the intrinsic
dissolution testing of APIs. Direct solid phase analysis in
tandem with measurement of dissolved concentrations enabled molecular level insight into changes in dissolution rate
due to hydrate formation. Against expectations, preferred
orientation of drug crystals during sample preparation was
shown to have only minor effects on dissolution results during intrinsic dissolution. Importance of dissolution medium
on solvent-mediated conversion kinetics was revealed as bile
salts were shown to be able to interact with the dissolving
solid by hydrogen bonding mechanisms. To predict in vivo
behaviour of BCS class II drugs, simple and cost-effective
34
conventional surfactant media were shown to be potential
substitutes for more complex, physiologically based Fasted
State Simulated Intestinal Fluid (FaSSIF).
This thesis provides directly applicable new tools for
the dissolution experiments in pharmaceutical drug development. In-depth information of solid state properties on
dissolution rate assists in drug candidate selection as well as
in explaining and controlling the behaviour of APIs in the
final drug products. The use of simplified, in vivo prognostic dissolution media has potential of saving development
time and costs for formulation development and regulatory
purposes.
Miniaturization of Drug Solubility
and Dissolution Testings
Tiina Heikkilä
University of Helsinki
ISBN 978-952-10-6191-2
Solubility and drug dissolution are of crucial importance
for drug formulations. Poor water-solubility of drug candidates is a major obstacle in drug development, since the oral
route is the most patient convenient and cost effective way to
deliver drugs. In some cases the low aqueous solubility may
limit the bioavailability when the absorption of the drug is
dissolution limited. About 40% of the current lead optimization compounds suffer from poor solubility.
Improvements in drug solubility/dissolution testing
technologies (e.g. high throughput screening, HTS) can
enhance the possibilities of the lead compounds to success
in the later stages of drug development process. Typically
HTS protocols measure the kinetic solubility involving cosolvents (e.g. dimethyl sulfoxide), which might enhance the
in vitro solubility or give erroneous results if the potential
drug candidates are eliminated. Also, measurement of dissolution profiles is not available by the present HTS methods. For these reasons, there is a need for improvements in
HTS solubility formats.
Traditionally the in vitro dissolution tests are studied by
pharmacopoeial methods, which are not utilizable in the
drug discovery stage because of the large amount of compounds needed. However, dissolution studies at the drug
discovery stage could be useful e.g. to classify compounds
based on their dissolution rates. In addition, the initial steps
of dissolution process might be lost by the regulatory dissolution methods.
The aim of this thesis was to miniaturize traditional drug
dissolution and solubility testing methods. Systematic down
scaling of methods was done towards the development of
both equilibrium and kinetic 96-well plate solubility/dissolution methods.
Miniaturization of the regulatory dissolution methods
and shake-flask solubility measurements on the 96-well
plates was successful. 96-well plate methods for equilibrium
drug solubilities, as well as for drug dissolution profiles as a
function of time, were developed. The former method is the
first true equilibrium solubility method, which can be used
in the screening of drug solubility and dissolution phenomena at the early stages of drug development process. This
method was also tested using fasted state human intestinal
fluid as a medium for the first time. Human intestinal fluid
and data obtained might turn out to be important for very
low water-solubility compounds. Surface tension based microtensiometry was also presented as an alternative method
for kinetic HTS of drug solubility properties, e.g. for classifying solubility of compounds not suitable for UV-analysis.
Channel flow methodology was introduced enabling especially the kinetic follow-up at the very beginning of the dissolution process.
This thesis provides directly applicable new miniaturized
methods for the drug solubility and dissolution experiments.
These methods enhance the throughput and understanding
of drug solubility/dissolution phenomena and profiles in
drug discovery and improve success in the later stages of the
drug development process.
rials were analysed by assaying the quantity of the reaction
product generated during enzymatic cleavage of the milk
sugar. A near-linear increase in the thickness of the drug
layer was obtained during progressive treatment. Using the
enzyme coating procedure, it was confirmed that the ultrasound-assisted technique is suitable for processing labile protein materials. In addition, this pre-treatment of milk sugar
could be used to improve utilization of lactose-containing
formulations for populations suffering from severe lactose
intolerance. Furthermore, the applicability of the thin-coating technique for improving homogeneity of low-dose solid
dosage forms was shown. The carrier particles coated with
API gave rise to uniform distribution of the drug within the
powder. The mixture remained homogeneous during further
tabletting, whereas the reference physical powder mixture
was subject to segregation.
In conclusion, ultrasound-assisted surface engineering
of pharmaceutical powders can be effective technology for
improving formulation and performance of solid dosage
forms such as dry powder inhalers (DPI) and direct compression products.
Ultrasound-assisted surface
engineering of pharmaceutical
powders
Natalja Genina
University of Helsinki
ISBN 978-952-10-6414-2
Effective processing of powdered particles can facilitate
powder handling and result in better drug product performance, which is of great importance in the pharmaceutical
industry where the majority of active pharmaceutical ingredients (APIs) are delivered as solid dosage forms. The purpose of this work was to develop a new ultrasound-assisted
method for particle surface modification and thin-coating of
pharmaceutical powders. The ultrasound was used to produce an aqueous mist with or without a coating agent.
By using the proposed technique, it was possible to decrease the interparticular interactions and improve rheological properties of poorly-flowing water-soluble powders by
aqueous smoothing of the rough surfaces of irregular particles. In turn, hydrophilic polymer thin-coating of a hydrophobic substance diminished the triboelectrostatic charge
transfer and improved the flowability of highly cohesive
powder. To determine the coating efficiency of the technique,
the bioactive molecule β-galactosidase was layered onto the
surface of powdered lactose particles. Enzyme-treated mate-
35
Itä-Suomen yliopisto
Farmasian teknologia
Kati Autio
Suspensiovehikkelien vaikutus nifedipiinin fysikaaliseen säilyvyyteen
lasten ex-tempore oraalisuspensiossa
Marko Honkanen
High shear -rakeistuksen siirtäminen teolliseen mittakaavaan
Okko Lehtinen
Alfa-tokoferolin käyttö stabilointiaineena lääkevalmisteissa
Henna Määttä
Huokoisen piin farmaseuttiset sovellukset ja turvallisuus
Johanna Palmgren
Laatuun vaikuttavat tekijät ja laadunvalvontatoimet nestemäisten ja
puolikiinteiden lääkevalmisteiden teollisessa tuotannossa
Armi Savolainen
Partikkelikoon reaaliaikaiset määritysmenetelmät rakeistuksessa
Henna Uusitalo
PLGA-nanopartikkelien kehitys lääkkeiden antoon keuhkojen kautta
Biofarmasia
Maija-Riitta Kauppinen
Geeninkuljettimien testaus in vitro: 4-dihydropyridiini (DHP) -johdokset
Varpu Lepikkö
Sairauksien vaikutus permeaatioesteisiin in vivo ohutsuolessa ja
permeaatiovastuksen jakautuminen in vitro solupermeaatiokokeissa
Meri Piispanen
Syöpälääkkeiden aktiivinen kohdentaminen liposomeilla
MSc theses 2010
Åbo Akademi
Kemiantekniikka
Ling Li
36
Synthesis and Hydrolytic Stability of Mesoporous Silica Nanoparticles
Turun yliopisto
Teollisuusfysiikka
Markus Lampainen
Termisesti karbidoidun huokoisen piin tutkiminen röntgenfoto- ja Augerelektronispektroskopialla
Joonas Meri
Valmistusparametrien vaikutus huokoisten piinanopartikkelien
kokojakaumaan
Helsingin yliopisto
Farmasian teknologia
Kaisa Knuutila
Gastro-resistant multiparticulate oral drug delivery
Riikka Korpilahti
Artikaiinihydrokloridin preformulointi ja artikaiinikurlausveden
kehittäminen
Maria Tahvanainen
Eläimille tarkoitetun transdermaalisen lääkevalmisteen kehittäminen
Teollisuusfarmasia
Helena Harju
Lääkkeellisen immunoglobuliinin puhdistamisen ja
kylmäkuivausprosessin optimointi tuotekehitysvaiheessa
Sanna Räntilä
Kissojen lääkintään liittyvät ongelmat
Biofarmasia
Elina Saarikko
Lääkeaineiden luokittelu biofarmaseuttisten luokittelujärjestelmien
mukaan, tapausesimerkki hydroklooritiatsidi
37
Pharmaceutical Solid State Research Cluster —
kiinteiden lääkemuotojen kansainvälinen tutkimusverkosto
Vuonna 2006 kansainvälinen joukko tieteentekijöitä eri yliopistoista keskustelivat kiinteän tilan, kiinteiden lääkemuotojen ja niiden valmistusprosessien
tutkimuksen asemasta. He olivat huomanneet kuinka
nanoteknologia ja biotieteet valtasivat alaa farmasian teknologian tutkimuskentällä, ja olivat huolissaan
kiinteän tilan ja kiinteiden lääkevalmisteiden tutkimuksen osaamisen jäävän näiden jalkoihin. Syntyi
ajatus kansainvälisestä tutkimusverkostosta, jonka
avulla kiinteän tilan tutkimusta voisi viedä eteenpäin
ja kehittää, ja jonka yhteistyön seurauksena tutkimuksen jatkuvuus olisi vahvempi. AAPS:n vuosittaisessa
kokouksessa Yhdysvaltain San Antoniossa päätettiin
perustaa Pharmaceutical Solid State Research Cluster
(PSSRC). Tavoitteena oli luoda tutkimusverkosto, jonka puitteissa alaa voitaisiin kehittää syventäen kiinteän tilan osaamista.
PSSRC:n perustajajäseniä ovat Helsingin, Kööpenhaminan, Düsseldorfin, Cambridgen, Otagon
ja Ghentin yliopistot. Vuonna 2008 tammikuussa ja
elokuussa PSSRC laajeni, kun Lillen ja Lissabonin
yliopistot liittyivät jäseneksi. Klusterin hallinnossa
on professoritason edustaja jokaisesta jäsenyliopistosta, ja hallituksen puheenjohtajuus kiertää vuosittain.
Vuosina 2011–2012 PSSRC:n puheenjohtajana toimii
professori Anne Juppo Helsingin yliopistosta. PSSRC
on verkostona varsin pieni, mikä on omiaan luomaan
läheiset suhteet jäsenyliopistojen välillä. Vaikkakin
laajennuksia on mahdollisesti luvassa vuonna 2011,
klusteri pyrkii pysymään hallittavan kokoisena, eikä
uusia jäseniä seuraavan laajennuksen jälkeen ole kaavailtu.
PSSRC:n kantavia ajatuksia on vastavuoroinen
yhteistyö. Tämä pitää sisällään yhteiset tutkimushankkeet, tutkijoiden vapaan liikkuvuuden, tiedon
vaihdon ja yhteisen laitekannan hyödyntämisen. Jokainen jäsenyliopisto voi rahoitushakemuksissaan
viitata PSSRC:n yhteiseen laitekantaan ja erikoisosaamiseen.
Klusterilla ei ole varsinaista taloudellista yhteistyötä, vaan yhteistyö perustuu vastavuoroisuuteen ja
yhteisen edun tavoittelemiseen. PSSRC:n tutkimus
kattaa laajasti kiinteiden lääkevalmisteiden valmistukseen liittyviä aiheita fysikaalisen farmasian alalta.
Klusterin tutkimus keskittyy analyyttisten menetelmi-
38
en kehittämiseen ja niiden soveltamiseen lääkkeenvalmistuksen prosesseihin. Ilmiöitä ja niiden taustalla
olevaa kemiaa ja fysiikkaa pyritään ymmärtämään
kokonaisvaltaisesti, ja saatua tietoa pyritään hyödyntämään kiinteiden lääkevalmisteiden valmistusprosessien hallitsemisessa ja optimoinnissa.
Klusteri pyrkii toiminnassaan olemaan aktiivisesti läsnä tutkijoiden ja jatko-opiskelijoiden arjessa.
Klusterin jäsenet ovat toteuttaneet yhteisiä projekteja, on ollut aktiivista tutkija- ja opettajavaihtoa ja on
julkaistu useita yhteisjulkaisuja. PSSRC on esimerkiksi saanut kokonaisen teemanumeron tieteellisessä
julkaisusarjassa European Journal of Pharmaceutics and
Biopharmaceutics (Eur. J. Pharm. Biopharm. 71(1)) ja
nyt on suunnitteilla uusi teemanumero mallintamisesta ja simuloinnista.
PSSRC:n vuosittainen symposium on monelle
nuorelle tutkijalle tärkeä tapahtuma. Symposium on
pääosin suljettu tilaisuus, jonne klusterin jäsenet ja
alumnit ovat tervetulleita. Symposiumin tarkoitus
on tarjota foorumi, jossa esitellään tutkimustuloksia
ja tutkimushankkeita. Suljetun tilaisuuden etuna on
se, että se mahdollistaa julkaisemattomien tulosten
ja ideoiden esittämisen kannustavassa ja keskustelevassa ilmapiirissä. Nuoret jatko-opiskelijat ovat symposiumissa näkyvässä osassa; he pitävät valtaosan
suullisista esityksistä. Monelle heistä symposium on
ensimmäinen kansainvälinen esiintyminen. Suljettu
symposium mahdollistaa rakentavan palautteen antamisen, ja antaa tärkeää kansainvälistä kokemusta
turvallisessa ympäristössä. Symposiumeja on ollut tähän mennessä neljä; viides symposium pidetään Helsingissä syksyllä 2011. Osallistuminen symposiumiin
on jäsenilleen ilmaista, jotta taloudelliset asiat eivät
vaikeuttaisi osallistumista. Tämän takia Helsingin
symposiumiin suunnitellaan lyhyttä klusteriin kuulumattomille osallistujille maksullista avointa sessiota
korkeatasoisilla luennoilla. Symposiumit ovat olleet
erittäin suosittuja, ja jatko-opiskelijat ovat halunneet
osallistua, jopa maksaen matkakulut itse.
Lisätietoa klusterin toiminnasta, kuten jäsenistä,
kokouksista, yhteishankkeista ja tutkijavaihdosta, löytyy Internet-osoitteesta www.pssrc.org.
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Farmasian opetus ja tutkimus Tarton yliopistossa
Jyrki Heinämäki (prof.)
Lääketieteellinen tiedekunta, Farmasian laitos, Tarton yliopisto, Eesti
Perinteikäs tiedeyliopisto
Tarton yliopisto on Eestin suurin ja vanhin yliopisto. Sen perusti Ruotsin kuningas Kustaa II Adolf
vuonna 1632 (ja tuolloin yliopisto sai nimekseen Academia Dorpatensis). Tänään Tarton yliopisto kuuluu
maailman yliopistojen vertailussa parhaimman 5 %
joukkoon (Lähde: QS-THES World University Rankings
2009 and 2010). Yliopistossa on 10 tiedekuntaa, 5 alueellista tutkimus-yksikköä ja useita eri erikoisalojen
tutkimuslaitoksia eri puolella Eestiä. Opetushenkilökunnan määrä on noin 1000, joista professoreita on
noin 170. Opiskelijoita Tartossa on kaiken kaikkiaan
lähes 20 000, joista noin 5 % on ulkomaalaisia.
Tarton yliopistossa Farmasian laitos kuuluu Lääketieteelliseen tiedekuntaan. Laitoksella on uudet nykyaikaiset tilat nopeasti kehittyvällä yliopiston uudella
kampusalueella lähellä Biomedicumia ja Tarton yliopistollista sairaalaa. Samalla kampusaluella sijaitsevat myös noin vuosi sitten valmistunut Kemian laitos
ja parhaillaan rakenteilla oleva Fysiikan laitos. Farmasian laitoksella työskentelee tällä hetkellä 2 professoria
(laitoksen johtaja prof. Peep Veski ja J. Heinämäki), 5
vanhempaa lehtoria, 2 vanhempaa tutkijaa, 3 yliassistenttia, 2 assistenttia sekä 3 väitöskirjatyön-tekijää.
Farmasian opetus ja tutkimus Tarton
yliopistossa
Tarton yliopistossa on mahdollista suorittaa farmasiassa proviisorin tutkintoon tähtääviä opintoja.
Farmaseuttien 3-vuotinen koulutus on järjestetty
Tallinnassa ammattikorkeakoulua vastaavassa oppilaitoksessa (”Tallinn Health College”). Tarton yliopistossa aloittaa joka vuosi 35 uutta proviisoriopiskelijaa
ja tutkinnon suorittaminen kestää noin 5 vuotta (300
ECTS). Opetusta annetaan seuraavissa farmasian
oppiaineissa: farmasian teknologia, farmaseuttinen
kemia, farmakologia, farmakognosia, biofarmasia ja
sosiaalifarmasia. Lääketieteellisessä tiedekunnassa on
40
mahdollisuus valita usean eri tohtoriohjelman välillä.
Tohtoriopinnot ovat laajuudeltaan 240 ECTS ja kestävät noin 4 vuotta.
Pääosin historiallisista syistä farmasian opetus ja
tutkimus Eestissä on kohdentunut perinteisiin oppiaineisiin ja uudet oppiaineet farmasiassa hakevat vielä
omaa paikkaansa ja suuntaansa. Farmakognosialla ja
farmakologialla on ollut aina vahva asema Tarton yliopiston farmasian opetuksessa ja tutkimuksessa. Farmakognosiassa tutkimusaiheet ovat liittyneet viime
vuosina mm. mustikan sisältämien eteeristen öljyjen
ja polyfenolisten aineiden määrittämiseen ja tutkimiseen sekä terpenoideihin. Farmakologian puolella
tutkimustyöt ovat olleet pääosin yhteistyöhankkeita
lääketieteellisen muiden laitosten kanssa liittyen mm.
Alzheimerin taudin syntymekanismeihin ja lääkehoitoon sekä vanhemisen yhteydessä tapahtuviin lihasten
metaboliamuutoksiin.
Farmasian teknologian opetusta on lisätty viime
vuosina proviisorin tutkinnossa ja tällä hetkellä oppiaineen kaikille yhteisten opintojen osuus (mukaan lukien galeeninen farmasia ja fysikaalinen farmasia) on 36
ECTS. Opetusta annetaan luentojen, harjoitustöiden
ja seminaarien muodossa ja farmasian teknologian
kurssit painottuvat lähinnä kolmannelle ja neljännelle
vuodelle opintoja. Lisäksi opiskelijoilla on mahdollisuus osallistua esimerkiksi seuraaville farmasian teknologian valinnaisten opintojen kursseille: ”Liposomit
ja nanopartikkelit”, ”Farmaseuttinen jauheteknologia”,
”Rakeistus- ja puristusteknologia” sekä ”Farmaseuttinen
ohutkerrospäällystys”. Farmasian teknologian alan tutkimus on kohdentunut (1) lääkeaineen ”solid-state”
-ominaisuuksiin ja niiden muokkausmahdollisuuksiin,
(2) haavan hoitoon tarkoitettujen lääkelaastareiden/
siteiden käsittelyyn ”elektrospinning” -tekniikalla sekä
(3) paksusuoleen lääkeainetta paikkaspesifisti vapauttaviin kapselivalmisteisiin. Tutkimustyötä tehdään
kiinteässä yhteistyössä ulkomaisten tutkijaryhmien
kanssa, mm. Helsingin yliopisto, Kööpenhaminan
yliopisto, Otagon yliopisto (Uusi-Seelanti) ja “Phar-
maceutical Solid State Research Cluster” (PSSRC). Laitoksen melko suppeasta lääkevalmis-tuslaitekannasta
johtuen, itse lääkevalmistusprosesseihin liittyvää farmasian teknologian tutkimusta ei ole tähän mennessä
ollut kovinkaan paljoa.
Sosiaalifarmasian alalla tutkimustyöt ovat käsitelleet apteekkiasiakkaiden käsikauppalääkkeiden käyttöä ja tietämystä mahdollisista haittavaikutuksista.
Farmasian laitoksen tuorein väitös oli joulukuussa
2010 juuri sosiaalifarmasian alalta eli Daisy Volmerin
apteekkien palvelutoiminnan kehittymistä käsittelevä
tutkimus ”The development of community pharmacy services in Estonia - public and professional perceptions 19932006”.
Yhteenveto
Tarton yliopistossa on farmasian alalla poikkeuksellisen paljon osaamista, lahjakkuutta, motivaatiota
ja sitoutumista sekä opiskelijoiden että henkilökunnan keskuudessa. Nykyään puitteet (tilat ja laitekanta)
laadukkaalle opetus- ja tutkimustyölle ovat niinikään
varsin hyvät. Uusia farmasian oppiaineita on otettu
näkyvästi proviisorin tutkintoon mukaan (esim. Fysikaalinen farmasia ja sosiaalifarmasia). Farmasian laitos on mukana myös kansainvälisessä henkilö-vaihtoverkostoissa, mikä luo hyvät edellytykset opiskelija- ja
tutkijavierailuille Tarttoon.
Fysikaalinen farmasia – uusi oppiaine Eestissä
Fysikaalisen farmasian opetuksen ja tutkimuksen
käynnistämiseen Eestissä on panostettu viime vuosina
paljon ja oppiaine on ollut myös Farmasian laitoksen
taholta yksi kehittämisen painopiste-alue. Varsin näkyvä rooli Eestin fysikaalisen farmasian opetuksen ja
tutkimuksen kehittämisessä on ollut FaT Karin Kogermannilla, joka on tuonut laitokselle sitä tutkimusosaamista, jota hän sovelsi omassa väitöskirjatyössään
Helsingin yliopiston Farmasian teknologian osastolla
vuosina 2004-2008. Fysikaalisen farmasian alueelta
järjestetään jo luentokursseja ja harjoitustöitä proviisori- ja jatko-opiskelijoille. Myös farmasian tutkimuksen seminaarisarjassa fysikaalisen farmasiaan liittyvät
esitelmät ja opinnäytetyöt ovat olleet vahvasti esillä.
Fysikaalisen farmasian tutkimustyö on keskittynyt mm. lääkeaineen eri kidemuotojen ja apuaineiden kiinteän tilan vuorovaikutuksiin, merkitykseen ja
muokkausmahdollisuuksiin lääkeaineen liukenemisen
kannalta. Farmasian laitoksella on tällä hetkellä erittäin hyvä tutkimuslaitekanta nimenomaan kemiallisen
ja fysikaalisen kiinteän tilan analytiikan osalta: NIR ja
Raman-spektroskopiat, DSC, HPLC, UV spektrometrit ja valomikroskoopit. Lisäksi samalla yliopistokampuksella on kemian laitoksen uusissa tiloissa mahdollisuus käyttää varsin monipuolista analyysilaitekantaa,
esimerkkinä mikroskooppi- ja kuva-analyysitekniikat
(mm. SEM, TEM, CLSM ja AFM).
41
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List of Participants
Jaakko Aaltonen
University of Helsinki
Aija Linna
JRS Pharma Oy
Tiina Andronoff
JRS Pharma Oy
Ermei Mäkilä
University of Turku
Lotta Bergman
Åbo Akademi University
Juha Mönkäre
University of Eastern Finland
Henrik Ehlers
University of Helsinki
Tuomo Nissinen
University of Eastern Finland
Tuomas Ervasti
University of Eastern Finland
Katja Pajula
University of Eastern Finland
Natalja Genina
Åbo Akademi University
Joakim Riikonen
University of Eastern Finland
Petteri Heljo
University of Helsinki
Ronald Roberts
AstraZeneca Ltd.
Kaisa Hämäläinen
Fimea
Niklas Sandler
Åbo Akademi University
Jukka Ilkka
Medfiles Ltd.
Sampada Sawant
Åbo Akademi University
Kristiina Järvinen
University of Eastern Finland
Pekka Savolainen
University of Eastern Finland
Maiju Järvinen
University of Eastern Finland
Simo-Pekka Simonaho
University of Eastern Finland
Martti Kaasalainen
University of Turku
Mikko Tenho
University of Turku
Esko Karkkonen
Malvern Instruments Ltd.
Päivi Tiihonen
University of Eastern Finland
Ari Kauppinen
University of Eastern Finland
Merja Valta
Orion Pharma
Jarkko Ketolainen
University of Eastern Finland
Marko Vauhkonen
University of Eastern Finland
Niina Kivikero
University of Helsinki
Jaana Veki
University of Eastern Finland
Kristiina Korhonen
University of Eastern Finland
Peter Vikegard
TA Instruments
Ossi Korhonen
University of Eastern Finland
Jouko Virtanen
JRS Pharma Oy
Satu Lakio
University of Helsinki
Reinhard Vollmer
JRS Pharma GmbH
Claus Larsen
TA Instruments
Marju Väkiparta
Orion Pharma
Vesa-Pekka Lehto
University of Eastern Finland
Swantje Völler
Åbo Akademi University
Johanna Lehtonen
Orion Pharma
Emrah Yildir
Åbo Akademi University
43
Yhdistys tiedottaa
Fysikaalisen farmasian 23. symposium
Fysikaalisen farmasian yhdistyksen vuosittaisen symposiumin järjestelykäytännöt muuttuvat. Vuoden 2011 Fysikaalisen farmasian yhdistyksen 22. symposium on järjestetty vielä vanhan yksivuotisen
mallin mukaan, mutta 23. symposium pääkaupunkiseudulla 2012 on suunniteltu uuden kaksivuotisen
järjestelymallin mukaan. Muutos kohdistuu ainoastaan suunnitteluaikatauluun, symposium tullaan
edelleen järjestämään vuosittain.
Yhdistys pyrkii muutoksella kasvattamaan symposiumien kotimaisten sekä ulkomaisten vieraiden
määrää. Saavuttaaksemme tämän tarvitsemme enemmän aktiivista mainostusta ja korkeatasoisen ohjelman. Tämän takia hallitus päätti siirtyä kaksivuotiseen järjestelymalliin. Toisin sanoen, tämän hallituskauden tavoitteena oli järjestää 22. symposium alusta asti vanhan mallin mukaan, mutta samalla
suunnitella 23. symposiumia vuodelle 2012. Tavoitteena oli vuoden aikana päättää 23. symposiumin
ajankohta, varata tilat sekä valita aihepiiri. Saavutettuamme tämän, uusi hallitus voisi keskittyä vuoden ajan ohjelman suunnitteluun, hyvien puhujien hankintaan ja aktiiviseen mainostukseen. Lisäksi
aloitamme 24. symposiumin (2013) järjestelyt. Lisäksi symposiumin taloudellista puolta pyritään jatkossa parantamaan hakemalla apurahoja, jolloin pidemmälle ehtineestä ohjelmasta on suuri hyöty.
Ensi vuoden symposiumaihe on edelleen avoin. Yhdistyksen jäsenillä on nyt mahdollisuus vaikuttaa
puhujiin ja aiheen tarkentumiseen. Pyydämme ehdotuksia, kommentteja ja toiveita, jotta voisimme
järjestää symposiumin joka on laajalti yhdistyksen jäsenistölle mielekäs!
The 23rd Symposium of Physical Pharmacy
The routines in arranging the annual symposium of the society of physical pharmacy are changing. The 22nd symposium in Kuopio 2011 was still arranged according to a one-year arranging cycle,
but the 23rd symposium in Espoo is going to be arranged a new two-year cycle. The change applies
only to the planning routines; the symposium is still going to be arranged annually.
Through this change, the society aims for enriching the symposium by attracting a larger number
of both domestic and international participants. To achieve this, we need more active promoting and
high quality speakers. This was the reason for changing to a two-year cycle in our symposium planning. Consequently, the goal of this year was to arrange the 22nd symposium from beginning to end
and in addition start to plan the 23rd symposium. We had in mind to publish the symposium venue,
date and general topic by this year’s symposium, and after achieving that the new executive committee
can concentrate on planning the program, recruiting quality speakers and active promoting as well as
starting to plan the 24th symposium (2013). In addition, we now have better possibilities to receive
grants to ease the financial burden of the symposium. The topic of the symposium is not yet defined.
The members of the society now have an opportunity to participate in the choice of speakers and in
specifying the general topic. We ask for your suggestions, comments and wishes to be able to arrange
a symposium that pleases our community!
44
S
STY
DI
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First Announcement - 23rd Annual Symposium
*
E
CI
23rd Annual Symposium of the
Finnish Society of Physical Pharmacy
February 9th, 2012 – Spektri, Espoo, Finland
The symposium attracts annually 60-100 participants from
academia, industry and regulatory authorities interested in
the latest developments in the field of physical pharmacy. The
programme includes talks, poster session and a banquet. The
theme of the 2012 annual symposium will announced in spring
2011.
www.fysikaalinenfarmasia.fi
Please visit the homepage of the Finnish Society of Physical
Pharmacy for the latest information on the symposium.
1988
OF
PHYSICAL PH
M
SO
TY
AC
Y
*
AR
EMPYREAN
Quality by Design (QbD) and scale-up studies
Slurry Flow Cell for in situ
crystallization studies
• Variation of crystallization conditions
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and hemi-hydrates
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-2
G(r) [Å ]
Investigation of crystallization stages
• SAXS for particle size and shape
• PDF for determination of local
structure
• XRD for phase identification and
crystallite size
• CT for 3D crystal morphology imaging
0 hours
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Crystallization of spraydried lactose (PDF analysis)
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T +358 9 2212 580
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The Analytical X-ray Company