CENTER OF KNOWLEDGE AND TECHNOLOGIES TRANSFER Elena Guseva 1 Natalia Menshutina 1, Hans Leuenberger 2 1 D.I. Mendeleev University of Chemical Technology

CENTER OF KNOWLEDGE AND TECHNOLOGIES TRANSFER

Elena Guseva1

Natalia Menshutina1, Hans Leuenberger2

1D.I. Mendeleev University of Chemical Technology of Russia

2University of Basel, Switzerland

In the beginning…

Russian-Swiss science and education center for transfer of biopharmaceutical technologies has been established on the basis of MUCTR as the result of team-work between the Institute of Pharmaceutical Technology, University of Basel and MUCTR.

The Russian-Swiss science and education center has the official status of the structural unit of MUCTR.

The Center is a new basis to enhance the Russian-Swiss relationship in education, science and technology transfer for mutual benefit.

The center was founded under support of:•Russian Ministry of Education and Science•State Secretariat for Education and Research SER •Swiss Embassy in Moscow

MAIN AIMS AND TASKS

• co-ordination of students education on special master courses using the Centre’s facilities, equipment and materials in accordance with European standards and technical requirements;

• organisation of specialised laboratories within the university for the purpose of conducting scientific studies profile;

• advanced training of specialists from appropriately profiled enterprises;

• publication of relevant successes and popularization of intellectual achievements of Russian and Swiss research organization to improve commercial appeal to the international market.

EDUCATIONAL ACTIVITY

• graduate unique specialists

• promote knowledge to practice

• cultivate understanding of technology

“We grow people for you”

INDUSTRYINDUSTRY UNIVERSITIESUNIVERSITIES

Technology + Equipment

Competent specialists

(Masters, PhDs)

TRAINING OF SPECIALISTS

Improvement of skills and training courses were developed for Russian pharmaceutical specialists:

• «Technologies and equipment for

pharmaceutical industry»

• Granulation, Drying, Coating (together with Glatt, Huettlin, BASF, Evonik)

• Quality management

• PAT

• …

WEB-PORTAL «PHARMACEUTICS ONLINE»

http://www.muctr.edu.ru/~cache/claroline

Availability

Quality

Usability

A lot of classified information, useful for education of specialists in pharmaceutics technology area:

• Videos (with audio explanations)• High-quality photos• 2D and 3D animations, explaining physical and chemical processes, processes taking place inside apparatus• Schemes of general types of apparatus• Textual information with binding hyperlinks• Technical descriptions of all the processes, useful in pharmaceutics technology

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БлокБлок наполнения грануламинаполнения гранулами БлокБлок наполнения грануламинаполнения гранулами

Схема

Сканер колпачков капсул

Блок наполнения гранулами

ФункционированиеФункционирование

СтадияСтадия 4, 6, 8:4, 6, 8: Блок наполнения гранулами или таблеткамиБлок наполнения гранулами или таблетками((дополнительнодополнительно))

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Блок наполнения таблеткой

Открытие капсул

Удаление дефектных капсул

Сканер тела капсул

Блок закрытия капсул

Блок очистки

Варианты заполнения

Перенос капсул

Блок выгрузки капсул

Выравнивание капсул

Блок наполнения порошком

Main menu

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Схема



Бункер

Винтовая мешалка

Набивающие поршни

Датчик уровня

Дозирующий диск

Агитатор

Кольцо порошка

ДвигательДатчик уровня/(опционально)

СтадияСтадия 5:5: Блок наполнения порошкомБлок наполнения порошком

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Main menu

COURSE MATERIALS. LECTURES

• Dosage dispersed forms (671 slides)• Solid drugs forms (~400 slides)• Liquid sterile drug forms (~250 slides)• Equipment and Technologies of Pharmaceutical Industry (~700 slides, 18 lectures)

01.04.2003 317

5.7 Rheogramm plastischer Systeme

D

D

Fliessgrenze Fliessgrenze

Bingham Körper Casson Körper (wird immer flüssiger)

01.04.2003 399

7.7 Franz Diff usionszellsystem

01.04.2003 336

6.2 Wasserabgabe über die Haut

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Схема



СтадияСтадия 4, 6, 8:4, 6, 8: Блок наполнения гранулами или таблеткамиБлок наполнения гранулами или таблетками((дополнительнодополнительно))

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Гранулы через дозирующий диск (вместо блока загрузки порошка):

Гранулы под действием тяготения опускаются в дозирующее отверстие. При изменении стадии гранулы не изменяются до тех пор пока не наполнится дозирующая ёмкость. Потом дозирующая ёмкость закрывается. Когда блок с капсулой становится для обмена, открывается заслонка и гранулы поршнем уплотняют в капсулы.

Характеристики системы: 140 ударов/мин

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OUR BOOKS• «Nanoparticles and nanostructured materials for pharmaceutics»

Menshutina N.V.

• «Information systems and databases for pharmaceutics»

Menshutina N.V., Mesheryakova T.V., Goncharova S.V., Mishina Y.V., Leuenberger H. – M., MUCTR 2002

• «E-learning on chemical engineering and pharmaceutical specialities»

Menshutina N., Mishina Ju., Guseva E., Leuenberger H., Chelnokov V. – М., publishing house of scientific literature, Kaluga 2007

Visits, Abroad Studying, Lectures

LAST 2 YEARS:LAST 2 YEARS:

Students - 8

Ph.D. Students – 14

Lecturers – 18

Abroad studying – 2

EXCHANGE OF KNOWLEDGE

EQUIPMENT

• HUTTLIN Mycrolab /HUTTLIN GmbH/• Mini-Glatt /GLATT International GmbH/• Spray drying equipment /NIRO/• Equipment for production micro- and nanoparticles

by dispersion /Own development/

• AMETEK Proline Process Mass Spectrometer• Reverse osmosis equipment R02-50/CP-HR

• Oil-Free compressor Atlas-Copco

• Compressor F.F.

• Vacuum compressor

• Bioreactor

• SKAN Isolator equipment• Sonotec Ultra-sonic nozzle

RESEARCH AND CONSULTING

• Pharmaceutics– Freeze, Spray, Supercritical drying– Dispersion– Coating– Granulation– Encapsulation

• Biotechnology– stress of microorganism– protein production

• Nanotechnology– drug delivery

Information technology– PAT, LIMS– Software development

Development of new technologies and Scaling-up:

ENCAPSULATIONENCAPSULATION

Encapsulation by coating in fluidized layer under super

critical conditions

Encapsulation by coating in fluidized layer under super

critical conditions

Protein encapsulation to biodegradable

microspheres using freeze drying technologies

Protein encapsulation to biodegradable

microspheres using freeze drying technologies

Mannitol

Dextran

Spraying

Freezing

Sublimation of fluidized

bed particles

Atmospheric freeze-drying with

active hydrodynamics

… is alternative process to classical vacuum freeze-

drying

The process has two stages: • the initial freezing at spraying of the solution• the sublimation of frozen particles at their fluidization

The initial freezing is done in a freezing cabinet, which is equipped with an ultrasonic nozzle that is capable of producing particles of 150 mm. The freezing temperature inside the cabinet was held at –60C. The 15% aqueous solution of mannitol is sprayed top-down against a cold air stream.

At sublimation drying stage of the process the frozen particles are held by fluidization, and this was performed in the modified Glatt apparatus. The process was carried out at a drying temperature of about -20ºC. The average time of the process was about 3 hours.

The main stages and description of the process

• intensive heat and mass transfer, high moisture removal rate due to active hydrodynamic regime

• reduced time of the process

• energy effectiveness in comparison with classical freeze drying under vacuum

• better control of the residual moisture content and temperature, important for pharmaceutical products

• product size and shape design for manufacturing of solid dosage forms and production of injection and inhalation dosage form

• possibility of continuous operation

The advantages of the atmospheric freeze drying with active hydrodynamics

The properties of the pharmaceutical products

• preserved of natural structure and nutrients

• pre-specified particle size (nano- or microparticles)

• high porosity

• high specific and internal surface area of particles

• solubility and bioavailability

• free flowing powder

• spherical particle shape

• …

Comparison of spray drying and atmospheric spray-freeze drying

Spray drying particlesSpray-freeze drying particles

Comparison of vacuum freeze- drying and atmospheric spray-freeze drying

• pre-specified particle size (nano- or microparticles)

• high porosity

• free flowing powder

• spherical particle shape

• product size and shape design for manufacturing of solid dosage forms and production of injection and inhalation dosage form

• possibility of continuous operation

Shape and Structure of Particle

Spray drying particlesVacuum-freeze drying particles

Atmospheric Spray Freeze Drying as an Alternative

Advantages:

The result is a highly porous free flowing powder (pellets) with instant solubility properties.

The high porosity of the pellets (up to 85%) and the nanostructured internal surface is ideal for the formulation of novel drug delivery systems for the lung.


Advantages:

Process is faster due to the better heat transfer and has a lower variability.

It is possible to combine the advantages of Nano- and Microtechnology.


Advantages:

ideal for the preparation of nanocomposite pellets for low water soluble drugs to enhance bioavailability of the drug.

ideal for the formulation of temperature and structure sensitive drugs such as Biologicals i.e. Pharmaproteins such as Interferons, Insulin.

TECHNOLOGY TRANSFER

equipment selectiondesign and scaling-up process flowsheet optimization

mathematical models

modeling tools

KINETICS

• Drying driving force

• Combined heat and mass transfer inside particle

• Interface processes

HYDRODYNAMICS

HEAT AND MASS TRANSFER IN APPARATUS

DETERMINATION OF STABLE OPERATION MODE

OPTIMIZATION DESIGN SCALING-UP CONTROL

Modelling of the atmospheric freeze drying with active hydrodynamics

Modeling of hydrodynamics, heat-and mass-transfer in apparatus

t 1 1 1

0

div V f dmM

;

t m

f div f V f

2 0;

t

C div C V f dmV V

M

10

;

The equations of mass, concentration preservation are:

1

d V

dtP

fmf dm F f V V dm

k k

MM

1 11 1

12 1 1 2 100

;

D V

Dt

Pf F2 2

20 12 2

The equations of impulse preservation are:

;dmiifqdmTTfa4

dm2

VVfdmVVffme

dt

dP

dt

Ud

M

0211

M

021T

2

M

0

212

M

02112

kl1

kl1

011

01

11111

2121T2

022

02

2222 iifTTfa4Dt

DP

Dt

UDmf

The equations of energy preservation are:

P T P T P RT

d

dt tV

D

Dt tV

mk k k k

1 10

1 2 20

2 10

1 2 10

1

11

22

1 1 2

, , ; ;

; , ;

;

P

/ ; i

Additional correlations are:

Height, m

Vel

ocit

y, m

/s

The drying kinetics

The driving force of process:

The drying rate: J = ∙X

The effective mass transfer coefficient: = Nu∙D/l

1 > 2 V

The main influencing factor on the value of the driving force of atmospheric freeze drying is the flow of injected heat into the product, and outflow of water at sublimation.

1

2

12

212

1

1

2

2

T2

VV

T

1

T

1i

TTX

The mathematical model solution

• The solution of equations system allowed to investigate the hydrodynamic and temperature regimes (gas and particle velocities, temperature, void volume etc.), heat and mass transfer in any point of the apparatus, as well as to determine the drying rate.

• Moreover, on the basis of the mathematical model it is possible to find parameters for stable operation of a dryer, for example the height of a fountain.

The example of the drying kinetics modelling in apparatus II for d=150 m, V1inlet=0,30 m/s

0

10

20

30

40

50

60

70

80

90

0 50 100 150 200

Time (min)

W, %

experimental data

freeze-drying stage calculated data

The apparatus design and scale-up the process

The comparison of energy efficiency of atmospheric and vacuum freeze-drying

Ins

tant

aneo

us e

nerg

y ef

ficie

ncy

Time, min

Vacuum freeze drying

Atmospheric freeze drying

12.07.2005 7th WORLD CONGRESS of CHEMICAL ENGINEERING 24

• the atmospheric freeze-drying with active hydrodynamics is an innovative technology for production of pharmaceutical nano- and micro- powders with pre-specified structure and properties

• the mathematical model based on the mechanics of heterogeneous media and non-equilibrium thermodynamics has been developed and verified to define main operation parameters

• on the basis of a mathematical model the drying simulator has been developed

• also, a energy efficiency analysis of atmospheric freeze drying was carried out; in comparison with classical freeze-drying it is more energy efficient

• the approach proposed allows modeling, design and control of the processes described

Conclusions

TECHNOLOGY TRANSFER AND PROMOTION

• Conferences• Seminars • Round tables• Exhibitions• Publications• Website• …

The Third Russian-Swiss seminar “Pharminnovations”

5-6 December, 2006

HÜTTLIN GmbH (Germany)

NOVARTIS (Switzerland)

BIOTECHNOLOGY 2009 16-20 March

«Quality management ─ key factor in the development of pharmaceutical industry»

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Московская медицинская академия им И.М. Сеченова

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Documents

CENTER OF KNOWLEDGE AND TECHNOLOGIES TRANSFER Elena Guseva 1 Natalia Menshutina 1, Hans Leuenberger 2 1 D.I. Mendeleev University of Chemical Technology