Project management and R&D

09. et 16.02.2011

Sabine Cullmann
Presentations 1: 12h-15h30
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Bernard Kopp, Vronique Hoppe, Vincent Fum Bruno Schneider, Mickal Nonnenmacher El Hamdouchi Hajar, Kibaka Rita, Marie Paule Kenmogne Yanyan Tian, Zhao Wei, Yo-Tzu Chang Benot Tanovan, Vadim Neguta, Luc Gassmann (13-14h) Nokia: Fodil Saadi, Imad Wahbi, Zeineb Aziz 3M: Tinting Yang, Zhengyu Lin, Jing Ren Dimitry Kravets, Lukas Jandau, Wenlian Lu Apple: Anthony Loewenguth, Thierry Fath, Stefien Amidi Airbus: Kim Marlne Le, Nht-Nam Le Dyson: Arnaud Toni, Maxime Thiery Nestl: Shen Huang, Xiaowen Ma, Jieting Zhang Arcelor Mittal: Anne Winter, Christiani Andriamanakiandrianana, Mat Ludwig BMW: David Stotz, Maxime Ginglinger
Presentations 2: 15h30-19h
15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. Google: Kamal Naha, Sonia Fertoul, Amine Malily Novartis: Charlotte Geng, Eric Bisselbach, Marie-Audrey Stempfer Sony: Valentina Kodeva, Mariana Plamadeala, Simona Balaj Novartis: Cynthia Balzer, Anas Schanden, Yonca Metin Rebecca Tang, Souhila Lahmar, Yassine Chadda EADS Munich: Fouzia Bounajra, Laurence Bardol, Azzedine Ezzaouia Camille Schohn, Caroline Schuh, Camille Schroth Novocure: Blagovesta Vodenicharova, Patrizi Paulus, Grigoriy Garber Danone: Pauline Pernot, Fanny Ehrhard, Hlne Daider Renault: Julie Hytry, Rachid Boumendjel, Alejandro Del Monte Sanofi-Aventis: Suzel Geissler, Laura Fritz, Stphanie Fuss Intel: Frdric Munck, Rosita Milenkova, Ivaylo Petrvski GlaxoSmithKline: Elhadji Mamadou Wade, Mohamed Yousfi Sanofi-Aventis: Mamouna Hlne Sanoko, Assatou Ada Faye, Sguwind Ame Kontogom

Program

1. 19.01.2011 : Project management and R&D 1 2. 26.01.2011 : Project management and R&D 2, Landscape of R&D 3. 02.02.2011 : Internationalization of R&D Strategy and organisation of R&D 1 4. 09.02.2011 : Strategy and organisation of R&D 2 5. 16.02.2011 : Strategy and organisation of R&D 3 6. 23.02.2011 : Presentations, 12-19h, Amphi 1 Deadline : 22.02.2011
Strategy and organisation of R&D
1. An interpretative framework: towards a topology of firm organisations and flexibilities
2. Globalisation: definition and measures 3. Globalisation and organisation: diversity
Globalisation and flexible firm
An analysis of the economical context An interpretation of globalization and flexibility A transcription into the organization of R&D

Purposes and objectives

Why global ?
Why flexible ? How to think about it as manager ?
An interpretative framework
Why ? It is necessary to characterize the context in which firms operate Necessary to compare and analyse the evolution To contextualize the definition of globalization and flexibility

ENVIRONNEMENT

Nature of Information / Knowledge
Demand Competition Technologies
Monitoring/decision Information Systems Organisation/Production
An interpretative framework: an example
Inf. elastic pure/perfect comp. Given prod. Function
Profit Maximisation None Production function
An interpretative framework: the proposal

Standardisation model Variety model Reactivity / Pro-Activity model
Standardisation model: the environment
Environment: - Demand - Homogeneous demand - Stable and growing - Competition - PRICE through ?

Economies of Scale

Standardisation model: the firm
Mass production - standardized product Long life-cycles of products and/or technologies Increasing division of labor Taylorian organisation of the firm Rigid automatisation

Standardisation model

Stable information Programmable decisions - Operations Research paradigm Independance between organisation and environment Scientific organisation of labor
Standardisation model: virtuous circle ?
Economic viability ? The Smithian endogenous growth (A. Smith 1776)

Increasing demand

Division of Labor

Decreasing prices

learning by doing, economies of scale

Increasing productivity

Standardisation model: flexible ?
Is it ? If so how ? Is flexibility feasible/necessary under certainty ?

Standardisation model

Variety model Reactivity / Pro-Activity model
Variety model: the environment
Environment: - Demand Frequently re-newed demand over a range of characteristics Need for complementary services - Competition PRICE through economies of scale but also PRODUCT DIFFERENTIATION through ?

Economies of scope

Variety model: the firm
Planned changes of the products Mastered life-cycles of product and/or technologies (but shorter) Increasing division of labor Multidivisional organisation of the firm Flexible automatisation

Variety model

Stable and mastered information Programmable decisions - Operations Research paradigm (higher complexity) Independance between organisation and environment
Variety model: virtuous circle ?

Economies of Scope

Variety model: flexible ?

Is it ?

If so how ?
Reactivity-Proactivity model: the environment

Environment: - Demand

Tailor made with uncertainty on demand characteristics and volume Rapidly evolving demand Service oriented

- Competition

PRICE through economies of scale but also PRODUCT VARIETY through economies of scope AND ?
Timing - reduced reaction time
Reactivity-Proactivity model: the firm
Integrated (Product - Service) approach Mastering time: delivery, design, production, through-put time and anticipation Integrated organisation (?)
Reactivity-Proactivity model
Turbulent information, high uncertainty Non - programmable decisions Complex environment and interdependent systems Inter-dependance between organisation and environment
Reactivity-Proactivity model: viability ? (1/8)

Economic viability ?

INTEGRATIONS

Reactivity-Proactivity model: viability ? (2/8)

Dynamic flexibility

Reduced reaction time (increased speed)
Third dimension: time (after volume and characteristics)
Reactivity-Proactivity model: viability ? (3/8)

COSTS (INDIRECT)

Reactivity-Proactivity model: viability ? (4/8)
Effects on costs structures and dynamics

Life cycle cost 100%

Induced Costs

Actual Costs

Research Dev. Prototype Indus.
Reactivity-Proactivity model: viability ? (5/8)

A DVANTAGES (POTENTIAL)

Reactivity-Proactivity model: viability ? (6/8)

Potential advantages

Value of Activities

Potential value

Asset Value Asset Value
Reactivity-Proactivity model: viability ? (7/8)

Market

Production

Design

Reactivity-Proactivity model: viability ? (8/8)

Markets

Globalization: definition and measures
How to define globalization ?
How to define it as a new phenomena ?
Standardisation model Variety model
Reactivity / Pro-Activity model
How to define globalization ? How to define it as a new phenomena ?

Global ?

Who is it ?
Which technology (-ies) ? Which sector (s) ?
High tech firm Size: very significant, both in terms of turn-over and employees Technology: one of the most important and significant in terms of general economical impacts Governance: one of the most efficient (international CEO, interfirm agreements, JV)
Country UK Cuba Russia India Australia UK France Belgium UK Italy Ceylon Australia Australia Argentina Germany Spain France South Africa Norway AustriaHungary Netherlands Denmark Finland Indonesia Glasgow Havana Moscow Tirhot London Paris Brussels Manchester Firenze Colombo Melbourne Sydney Buenos Aires Berlin Barcelona Les Madeleine Johannesburg Kristiania (Oslo) Wien Den Haag Copenhagen Helsingfors Soerabaya

Office X X

X X X X X X X X X X X X X X X X X X X X X X
Number of contrats in a given period of reference (exports only)
Country France Russia Cuba Spain Germany Italy India Argentina Australia Ceylon Belgium Brazil Austria Holla nd Sweden No. of contracts 12

Who is it ?

Global ? Babcock & Wilcox Co.
Global ? Or Backcock & Wilcox Ltd

B&W: few dates

1856: Stephan Wilcox and O.M. Stillman patent water tube boiler 1866: S. Wilcox + G.H. Babcock patent safety boiler 1867: Partnership formed B&W and Co. 1870: reformed B&W 1881: Shareholding company B&W Co. 1891: The branch of Scotland transformed into shareholding company B&W Ltd. 1900: reorganisation with UK subscribed capital

B&W: main elements

Independent companies B&W Co. (NY) and B&W Ltd. (Glasgow) Global agreement on the allocation of the world market Strong cooperation in R&D: shared patents, exchange of qualified personnels, exchange of strategic informations, strong interfaces in strategies Sharing of cost AND benefit of innovative activities Strong awareness of knowledge as a strategic asset 59

Year 1881 1882-83

Agents and offices outside US (1881-91)

1884-85

Country UK Cuba Russia India Australia UK France Belgium UK Italy Ceylon Australia Australia Argentina Germany Spain France South Africa
Agent Glasgow Havana Moscow Tirhot London Paris Brussels Manchester Firenze Colombo Melbourne Sydney Buenos Aires Berlin Barcelona Les Madeleine Johannesb urg Kristiania (Oslo) Wien
X X X X X X X X X X X X X X X X

1886 Ca 1887-88

1890 1890-91

Norway

X X X X X X
AustriaHungary Netherland Den Haag s Denmark Copenhage n Finland Helsingfors Indonesia Soerabaya
Export contracts from the Glasgow branch to countries outside the UK in the period Oct. 1881- 17 May 1891 (job numbers 1-1262) Country No. of contracts
France Russia Cuba Spain Germany Italy India Argentina Australia Ceylon Belgium Brazil Austria Holla nd Sweden
Babcock & Wilcox Ltd. Subsidiaries/Acquisitions 1898-1923 Year 1898 Location France Societe Francaise des Constructions Babcock & Wilcox Germany Deutsche B&W Dampfkessel Werke AG Schafers Boiler Wo rk, Oberhausen (acquired) UK Japan UK Source: B&W arc hives. S pain Australia

Stirling Boiler Co. (acquired) Zemma wo rks E. Danks & Co (acquired)
B&W: knowledge management
Shared R&D activities and results (IPR management) Litigations and threats of litigation (towards competitors AND clients) Awareness about nature of knowledge and its competitive advantages
Strategic use of litigations If we lose, it will have the effect - knowing how long you can continue one of these suits - not only of checking (or stopping) the infringers for a considerable length of time, but also, and which is more important - (checking/stopping) buyers. He (H. Knight) pointed out that it was not difficult to find basis for such a suit and that B&W could stretch it out for a considerable length of time. This would be advertisement which was not to be despised. The fact of B&W Co suing imitators speaks for itself !
B&W: awareness of the nature of knowledge
We have no particularly valuable patents, that is intrinsically. The value of our patents applies in the completeness of our organisation. It is true that the word patent has its effect upon the public in general, and that it may be assured, more especially on this side of the water (Europe), that thefts of patents are not frequent. We need not have any fear on this score, in as much as our patents are not such as to tempt. A special plant, and knowledge, is required for our construction, and there is no likelihood that anyone will embark in a competitive businessas a manufacturing concern we cannot be sellers of patents. Babcock & Wilcox archive, UGD/309/3/20/3, Corr. Ch. Knight to B&W Co New York, 6/3-1889.

Global ? Case 2

Leader on the world market Sector: very competitive and price-driven 2000: - about 4000 employees, and still growing - 60% exports, branches/offices in 120 countries, 14 affiliates abroad

Very efficient

Ratio Firms in the Turnover/empl same sector oyee XXX Y Z 200 k 97 k 105 k Firms in Ratio different Turnover/emp sectors loyee LVMH L'Oreal Sagem 230 k 190 k 90 k

Permanent innovation process
1500 references 10 to 15 new products in the market/year in the last 20 years About 80 on-going projects
Design and production in one single country
Belongs to the large holding (with similar products)

TEFAL - T-FAL

1954: Marc Grgoire, a french engineer invents a process for bonding PTFE (PolyTetrafluorEthylne) with aluminum thus making the first non-stick pan
1958: The TEFAL company in founded in Sarcelles (France). By the end of the year, Tefal is making 100 pans a day and selling them with one claim: The Tefal pan: the pan that really doesnt stick
1961: In New York, a magazine publishes a photo of a rich and famous American woman bying a Tefal frying pan at Macys. American orders soar to 7500 pans a week just ten days later, demand has reached 1 million 73 units a month !
1968: Tefal is Frances n1 manufacturer of cookware with sales of FF49 millions. It is acquired by the french domestic appliances company SEB
1974: T-Fal diverfies with a gas lighter and a waffle/sandwich toaster
1981: T-Fal launches a world exclusive: an iron fitted with an electronic thermostat 1982: T-fal launches Sprintkeetle, its first electric kettle aimed at the UK market

TEFAL T-FAL

1987: T-Fal launches the first coolwall plastic deep fryer 1988: T Fal brings out a new cookware concept: Ultrabase, with the Ultra T-Plus non-stick coating, now twice as resistant 1990: T-Fal introduces Aquagliss, the first iron range with an integrated anti-scale protection 1994: T-Fal invents Armaral the pan that stands the test of time (more resistant to warpong and scratching). The same year T-Fal introduces the first deep fryer with a removable non-stick bowl
1995: T-Fal introduces the Clipso pressure cooker with the worldwide exclusive One Hand locking and opening mechanism 1996: T-Fal introduces Ingenio a complete set of cookware which comes with a removable handle for easy stacking up 2000: A new invention has burst on the scene: ThermoSpotTM the first heat indicator built into the frying pans non-stick coating 2002: T-Fal introduces Kaleo, an ingenious food processor with a box to store all its accessories

http://www.tefal.fr

Bodymaster Silhouette
L'quilibre la porte de tous !

Plaza Palla

Multi Wok

Tajine

Retrouvez le got des recettes traditionnelles
Toute une gamme de produits pour assurer le bien-tre de l'enfant et rassurer totalement les parents

Pse-Bb lectronique

Indispensable pour suivre la croissance de bb

Digital Watch Babyphone

La surveillance la plus complte et la plus confortable

Thermomtre de bain

Une scurit anti-brlure et une lecture facile
T-Fal designs products for your home. But it goes further. It aims at providing services that will deliver a total and rewarding experience, particularly when it comes to cooking. Life is meant to be lived with family and friends. Cooking is one of the great pleasures of life. The kitchen is one of the home's favourite rooms. This is why T-Fal aims at offering cooking recipes, advice, lessons and tools to enjoy those moments of pleasure to the full.

B&W vs. TEFAL

Who is global ?
What is new in the notion of globalization ?

Globalization ?

Sells ? Markets ? Finance ? Production ? Design ? Research and Development ?
More an analytical concept !
Standardisation and Variety: Supply-oriented; stable information; with an endogeneous mechanism of economical viability
Reactivity - Pro-activity: Demand oriented, high uncertainty, with an economical viability based on design and expectations
Globalization: measurements
If globalization is related to design and innovativeness Then:
Localisation of R&D expenditures Localisation of patents inventors Localisation of citations in patents
How important is the phenomena ?
Globalisation: measurements

Global assessments

Countries Sectoral views

Global assessments

US retains strong position in S&T
Share of total OECD R&D
Share of world patent families

1998 1991

United States

European Union

Other OECD

Rest of world

Source: OECD MSTI Database, January 2004
The rise of the rest: R&D investments are growing globally.

Among OECD countries

Korea Canada 4.5 4.0 3.5 Sweden Denmark Austria Finland

And non-Member countries

12,897 10,902 1,972 57,144

R&D in US$ (2001)

3.0 2.5 2.0

1.5 1.0

0.0 China Russian Federation Chinese Taipei Singapore

Globalization: 12 % ?

Jerry Sheshan, OCDE, 2004

Georg Licht, Recent Trends in Innovation Policy in Major OECD Economies Towards the Lisbon objective?
Share ofForeign MNE R&DinBERD (%) Share of MNE`s in BERD (%)
Finland Netherlands Sweden Canada UK France Germany Japan US
Share of R&D performed abroad by Germany Share of R&D abroad in T otal R&D of German Companies companies (%)
Total Transport Equipment Engineering Mechanical Engineering Chemicals

Globalization: Sweden

The case of an old industrialised country
Development of a specific typology
Internationally duplicated

Dispersed

Internationally diversified

Home-centered

Dernier dlai pour envoi des projets par e-mail :

22.02.2011

23.02.2011 :Presentations, 12-17h, Amphi 1
sabine.cullmann@unistra.fr FSEG, bureau 20 53

ORIGINAL PAPER

The influence of the extrusion die on pellet characteristics
RABIKOV M., WEINGARTOV D., HRING A. Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic Received: 21 November 2006 / Accepted: 18 December 2006 / Published online: 20 February 2007
SUMMARY The influence of the extrusion die on pellet characteristics Characteristics of pellets (pellet size distribution, their mean diameter, density, hardness, friability, repose angle, Hausner ratio, and drug dissolution profiles) prepared by axial and radial extrusion/spheronization were examined in this experimental study. The formulation consisted of binary mixtures of theophylline, a drug slightly soluble in water, and Avicel CL 611 as an excipient. Different characteristics were found in the samples prepared using the different extrusion dies: the axially situated extrusion die produces the pellets of higher hardness and density, and slower dissolution profiles. Differences in drug dissolution profiles should be considered, nevertheless they are not significant. All pellet samples showed low friability and excellent flow properties. Key words: pellets theophylline Avicel CL 611 extrusion/spheronization axial extrusion radial extrusion es. slov. Farm., 2007; 56, 1720 M
SOUHRN Vliv extruzn pepky na jakostn parametry pelet Experimentln studie sledovala vlastnosti pelet (distribuci velikosti stic, prmr pelet, jejich hustotu, pevnost, odr, sypn hel, Hausnerv faktor a disolun profily liva) pipravench axiln a radiln extruz/sferonizac. Pelety obsahovaly theofylin jako livo tce rozpustn ve vod a Avicel CL 611 ve funkci pomocn ltky. Vlastnosti peletovch vzork formovanch rozdlnou extruzn pepkou byly rzn: axiln situovan pepka produkovala pelety s vy hustotou a pevnost a pomalejmi disolunmi profily. Rozdly v uvolovn liva by se nemly opomjet, pestoe nebyly vznamn. Vechny peletov vzorky vykazovaly nzk odr a vborn tokov vlastnosti. Klov slova: pelety theofylin Avicel CL 611 extruze/sferonizace axiln extruze radiln extruze es. slov. Farm., 2007; 56, 1720
Corresponding author: doc. PharmDr. Miloslava Rabikov, CSc. Department of Pharmaceutics Palackho 13, Brno e-mail: rabiskovam@vfu.cz
ESK A SLOVENSK FARMACIE, 2007, 56, No. 1
Introduction Development of pharmaceutical dosage forms with increasing therapeutic efficacy and safety is a current trend in the pharmaceutical industry. Pellets belong to oral dosage forms providing these advantages. They can be formed using several different techniques. One of the most often used methods in the pharmaceutical industry is extrusion/spheronization 1). This process does not require inactive cores as a starting material and pellets containing up to 90 % of the active ingredient can be prepared 2). Extrusion/spheronization involves four steps: preparation of the wet mass (granulation), shaping the wet mass into cylinders (extrusion), breaking up the extrudate and rounding of the particles into spheres (spheronization), and finally drying of the formed pellets. All these steps are dependent on each other and are joined by a number of formulation (properties of the active ingredients and the excipients, their concentration in the formulation, properties and amount of the wetting agent) and process variables (method of moisturizing, type of extruder, thickness and type of the extrusion die, speed and time of the spheronization, method of the drying etc.) 3, 4). The object of this study was to observe the influence of the axial and radial type of the extrusion die together with the different size of its perforations on the characteristics of theophylline pellets. Theophylline was chosen as a model drug because of its low solubility in water. Microcrystalline cellulose, Avicel CL 611 type, was the second substance in the formulation. Microcrystalline cellulose is an excipient very often used in pellet production because of its lubricant, adsorption, antiadhesive, spheronizationenhancing, and compression properties. Avicel CL 611 contains, besides microcrystalline cellulose, also 15 % of carboxymethylcellulose sodium. Microcrystals of microcrystalline cellulose, insoluble in water, are leashed together with chains of soluble carboxymethylcellulose sodium to form meshlike powder particles, readily dispersed in water. Due to a small size of the microcrystals (approximately 60 % of the crystallites in dispersion are <0.2 m), there are a large number of microcrystals packed in each powder particle. These types of Avicel (RC, CL) are reported to slow down the drug release as they form a colloidal thixotropic gel layer controlling the drug dissolution 5). Combination of binary mixtures of a slightly soluble drug (8.3 g in 1.0 L of water at 25 oC 6)) and Avicel CL 611 was considered to decrease the drug release even more, when formed into pellets, to show best the possible changes in theophylline dissolution profiles from prepared samples with expected different characteristics.

tion enhancer, and purified water (Ph.B., Ph.Eur.) was the wetting agent. Pellet preparation The powder mixture (250.0 g) was first blended and then gradually wetted with water (115.0 g) in a mixer (Tefal Kaleo, France): 50 ml of water/min. Extrusion was performed on a onescrew axial or radial extruder (Pharmex 35T, Wyss & Probst, Germany). The plastic mass was fed through the hopper on a rotating screw at a standard extruder speed of 110 rpm. The diameter of perforations in the extrusion die was 0.8 mm and 1.0 mm, respectively, its width being 1.0 mm. A 200 g load of the extrudate was placed into a spheronizer (Pharmex 35T, Wyss & Probst, Germany) with a 23 cm diameter serrated plate. The spheronization speed was 640 rpm and spheronization time was 15 minutes. After spheronization, the pellets were dried using a ventilated oven (Hoffman, Type 0488, Germany) at 80 oC for 3 hours. Pellet characterization The size distribution of prepared pellets was determined by sieve analysis, using standard sieves with apertures in a range of 0.252.0 mm (Retsch, AS 200, Germany). The pellet mean diameter was calculated from the results of sieve analysis by applying the following formula 7): d=

xini 100

where xi is the mean of the upper and lower limits of the sieve fraction and ni is the percentage of the i fraction. Pellets of sizes from 0.8 mm to 1.25 mm were used for further characterization. For each sample of pellets, pycnometric density was determined by the gas displacement technique using a helium pycnometer (Pycnomatic ATC, Porotec GmbH., Germany) and helium as the intrusive gas according to Ph. Eur. 4. The test is intended to determine the volume occupied by a known mass of the powder or particles (7.510.5 g depending on the volume; the cell No. 30) by measuring the volume of gas displaced under defined conditions. The sample volume is determined after degassing the examined powder mass or particles and its pressurization using the following formula: Vs = Vc

Vr , Pi Pr 1 Pf Pr

where Vs is the sample volume, Vc is the cell volume, Vr is the reference volume, Pi is the initial pressure, Pr is the reference pressure, and Pf is the final pressure. The density of the powder mass is given by the equation:

EXPERIMENTAL

Materials Theophylline monohydrate (Lehmann and Voss, Germany) was the model drug, microcrystalline cellulose Avicel CL 611 (FMC, USA) was the filler and spheroniza-
The test was repeated three times. The pellet hardness was tested in a Tablet Hardness & Compression Tester (Engineering Systems, England) fitted with a C 5 load cell for pellet evaluation. The average hardness of 10 single pellets was calculated 8). The pellet friability was measured in an adapted Roche friabilator (type TAR 10, Erweka GmbH, Germany). 10 g of pellets were rotated in a stainless steel abrasion drum along with 200 pieces of 4-mm glass beads for 10 minutes at 20 rpm. The dust was thereafter removed and pellets were reweighed. The friability, i.e. the weight loss after agitation, was expressed as a percentage 8).

The repose angle represented the flowability of produced spheres. 50.0 g of pellet sample was placed in a glass funnel with a stem. The funnel was maintained upright so that the stem terminated 10 cm above a flat solid underlay protected from vibrations. Pellets flowed out of the funnel and formed a cone. Its height h and base diameter d were measured. The repose angle value was calculated using the following equation 8): = arc tg (2 h/d). The friability and repose angle of pellet samples were carried out in triplicate and the results were expressed as an arithmetic mean standard deviation. The Hausner ratio 9) was calculated from the pellet tapped and bulk densities according to equation: HR =
where HR is the Hausner ratio, t is the tapped density, and b is the bulk density of the particles. Dissolution profiles of the drug were determined using the basket dissolution method, 1000 ml of distilled water as the dissolution medium at 370.5 oC, and basket speed 50 rpm (Sotax, AT 7 Smart on-line, Switzerland), and evaluated spectrophotometrically (Perkin Elmer, UV/VIS spectrophotometer, USA) at 273 nm.
both in the axial position; samples 3 and 4 with extrusion dies of 0.8 and 1.0 mm perforations diameters, respectively, in a radial extruder. The smaller diameter of the extrusion screen perforations produced, according to our expectation, pellets of a smaller mean diameter of 0.95 mm (sample 1) and 0.94 mm (sample 3) in comparison to 1.14 mm and 1.13 mm mean diameter of samples 2 and 4 (Table 1). The yield of the pellets was high, in between 82.7 and 98.2 %, as well as the yield of the requested size fraction (within the range from 0.80 mm to 1.25 mm) above 76.7 % (Table 1). Pellets prepared using the axial extrusion die showed higher hardness values of 10.67 and 11.18 N vs. 8.06 and 8.54 N in the case of the radial die position (Table 2, Figure 1). Also the pellet density was higher in the samples prepared through the axially situated die compared to the pellets formed with the radial extrusion die (Table 2). Higher values of these parameters are caused by generating a higher pressure on the plastic mass during axial extrusion 2). Pellet hardness and density values also differ depending on extrusion die perforations (Table 2,

RESULTS AND DISCUSSION

Four batches of pellets containing 75 % of theophylline monohydrate and 25 % of Avicel CL 611 were prepared by extrusion/spheronization: sample 1 using an extrusion die of 0.8 mm perforations diameter, sample 2 with an extrusion die of 1.0 mm perforations diameter,
Table 1. Pellet size distribution Sample <0.25 (%) 0.5 0.0 0.2 0.5 0.250.50 (%) 3.9 0.9 1.0 1.1 Size distribution (mm) 0.500.80 (%) 15.6 4.9 15.1 2.6
Figure 1. Influence of the extrusion screen on pellet hardness
Mean diameter (mm) 0.801.0 (%) 37.5 20.1 52.2 11.5 1.01.25 (%) 39.2 56.8 29.7 73.3 >1.25 (%) 3.3 17.3 1.8 11.0 0.95 1.14 0.94 1.13

Table 2. Pellet physical properties Sample Pycnometric density* (g/cm3) 1.3420.014 1.3370.007 1,3320.008 1,3290.018 Hardness** (N) 11.181.26 10.671.13 8.541.68 8.062.55 Friability* (%) 0.100.02 0.070.02 0.050.02 0.080.01 Repose angle* (o) 25.400.55 26.300.21 23.120.94 22.500.53 Hausner ratio 1.03 1.01 1.02 1.03
* average from three measurments ** average from ten measurments
Table 3. Theophylline dissolution profiles Sample 15 min 37.16 0.13 32.65 0.20 45.26 0.21 32.21 0.12 Amount of released theophylline (%) 30 min 45 min 60 min 67.85 0.21 64.49 0.10 80.77 0.13 65.95 0.17 82.00 0.16 81.59 0.24 94.38 0.18 85.38 0.22 88.66 0.26 89.27 0.09 98.88 0.17 94.18 0.23
75 min 92.79 0.14 93.00 0.19 99.85 0.28 98.55 0.15
90 min 95.40 0.24 95.19 0.17 99.87 0.15 99.54 0.28
Figure 2. Theophylline dissolution profiles from samples 1 and 3 (die openings diameter 0.8 mm)
Figure 3. Theophylline dissolution profiles from the samples 2 and 4 (die openings diameter 1.0 mm)
Figure 1). Pellets of higher hardness and density were manufactured by forcing the extrudate through the extrusion screen with 0.8 mm perforations. The reason is greater densification of the material caused by a higher pressure during extrusion through the smaller die openings. All samples of the formulated pellets had very low friability below 0.10 % (Table 2) proving their appropriate mechanical properties and good ability for further processes (e.g. coating, filling, compression, and transportation). Hausner ratio with a value close to 1.0 (advert to small differences between bulk and tapped densities) guarantees trouble-free capsule filling of pellets into hard gelatine capsules, and good achievement of required weight uniformity. Good flow properties of pellets are confirmed also by the low values of the repose angle, below 26o 20 (Table 2). Drug dissolution profiles showed that theophylline was released more slowly from pellets prepared by axial extrusion (Table 3, Figures 2 and 3). These results indicate that slower drug release could be achieved from more compact pellets with higher hardness and density values. However, the found differences, especially in samples 2 and 4 (Figure 3), are small. Theophylline was completely released from all samples within 90 minutes. We can conclude that the axially situated extrusion die produces pellets of better physical properties (hardness, density). The differences in drug dissolution profiles
should be considered, nevertheless they are not significant.
This experimental study was supported by IGA VFU Project No 15/2004/FaF.

REFERENCES

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