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PEARLITOL ® M A N N I T O L F O R P H A R M A C E U T I C A L A P P L I C A T I O N S q 12016Brochure PEARLITOL-Anglais_Brochure PEARLITOL-Anglais 19/06/12 14:56 Page1
P E A R L I T O L m a n n i t o l ...... mannitol. . . . S U M M A R Y
• Introduction...... page 2
• Description ...... page 3 - Molecular weight - Formula - Conformities
• Physiological properties...... page 5 - Sweetness - Safety - Metabolism and tolerance - Dental aspects
• Physical and chemical properties ...... page 7 - Stability - Solubility - Hygroscopicity - Osmolality - Crystalline forms - Melting point - Spectrometry Infrared absorption Spectra NMR Spectra
• Functional properties and applications ...... page 11 - PEARLITOL® mannitol crystalline powders - PEARLITOL® mannitol granular powders
® • PEARLITOL PF ...... page 19
® • PEARLITOL Packaging ...... page 20
® • PEARLITOL International technical support ...... page 20
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I N T R O D U C T I O N ......
Roquette is one of the leading companies providing starch derivatives and polyols and has developed a wide range of products and services especially dedicated to the pharmaceutical and cosmetic industries. Based on this experience Roquette has been widening its range of polyol excipients through technical innovations, combining quality with performance. Roquette offers a wide range of polyols and amongst them, PEARLITOL mannitol. PEARLITOL is a brand name of a range of mannitol dedicated to the manufacture of medicines. Mannitol presents the following features: ➢ Very low hygroscopicity: it does not promote hydrolysis reaction. ➢ Very high chemical stability due to its polyol structure, mannitol does not undergo reducing reaction or discoloration reaction with amino groups (Chemical Inertness). ➢ Wide range of possible applications: ➢ For different forms: - injectable (in solutions or freeze dried) - oral (tablet, chewable tablet, fast dissolving tablet, hard capsule, sachets). ➢ For different processes: - wet or dry granulation - direct compression - freeze-drying.
Moreover, mannitol is non cariogenic and allows sugar free formulation. Mannitol offers unique physical and chemical characteristics and superior performances, making it the best choice in excipients.
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D E S C R I P T I O N ......
Mannitol takes its name from manna, CHO CHO CH2OH CH2OH
a sweet exsudate from OH HO OH HO
HO HO HO HO the manna ash (Fraxinus H + 2 + OH OH Ni OH OH ornus), of which it is OH OH OH OH the major constituent. CH2OH CH2OH CH2OH CH2OH Mannitol also occurs Glucose + Mannose Sorbitol + Mannitol in olives, figs and larches, in certain species of edible Mannitol and sorbitol are separated by their difference in fungi, and in seaweed aqueous solubility (water is the only process solvent). The (laminaria species). isolated mannitol is a white crystalline powder of very high purity. It is further transformed into a complete range of D-mannitol was originally PEARLITOL mannitol powders which is manufactured obtained industrially in a dedicated ISO 9002 certified plant. by an extraction process. The range of mannitol consists of 8 different grades: Whereas, since the ➢ PEARLITOL 160 C standard mannitol beginning, Roquette has ➢ PEARLITOL 50 C fine grade PEARLITOL 25 C very fine grade developped a manufacture ➢ ➢ PEARLITOL PF pyrogen free grade process of mannitol based ➢ PEARLITOL 100 SD spray-dried grade for direct upon starch, natural raw compression material of vegetable ➢ PEARLITOL 200 SD spray-dried grade for direct compression origin. Starch is ➢ PEARLITOL 300 DC fine granulated grade for transformed into a glucose direct compression mannose solution which ➢ PEARLITOL 400 DC medium granulated grade for direct compression gives mannitol through ➢ PEARLITOL 500 DC coarse granulated grade catalytic hydrogenation for direct compression according to the following reaction:
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D E S C R I P T I O N ...... M. olecular weight Formula
Mannitol is a polyol with a molecular weight of 182.17 and its empirical formula is C6H14O6. The chemical structure is the following:
CH2OH HO
HO
OH OH
CH2OH
Mannitol is registered under CAS number 69-65-8 and EINECS 200-711-8...... C. onformities
PEARLITOL mannitol comply with the mannitol monographs of the different pharmacopeia including: ➢ European Pharmacopeia ➢ USP ➢ Japanese Pharmacopeia
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P H Y S I O L O G I C A L P R O P E R T I E S ...... S. weetness
The following diagram compares the sweetness of mannitol with sucrose and annitol occurs M different polyols: naturally as a slightly Polyols’ sweetness . . . .
sweet white crystalline ......
1 ......
powder, that gives a . . . .
0.8 ......
cooling sensation in 0.6 ......
0.4 ......
the mouth......
0.2 ...... 0 . . . .
Sucrose Mannitol Sorbitol Maltitol Xylitol
Mannitol is approximately half as sweet as sucrose or xylitol...... S. afety
The joint FAO/WHO Expert Committee on Food Additives (JECFA) has decided in its 30th report (1987) not to specify an acceptable daily intake for mannitol. This means that mannitol is safe. This decision was based on a complete biotoxicological file. In Europe, the Scientific Committee for Food (SCF) has followed JECFA’s decision in 1989 regarding the acceptable daily intake.
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P H Y S I O L O G I C A L P R O P E R T I E S ...... M. etabolism and tolerance
A minor part of the ingested mannitol is partially absorbed and metabolised. It is passively absorbed in the upper gastrointestinal tract (as opposed to glucose which is actively absorbed). Mannitol is then partially oxidised into D-fructose by mannitol dehydrogenase and metabolised through a non insulinic glycogenolytic pathway. The major part of the ingested mannitol is not absorbed and goes through to the colon where it is fermented by the colonic microflora. The mannitol which is absorbed is non metabolised, and is directly excreted through the kidney in the urine. The ingestion of mannitol in large quantities can lead to flatulence, laxative effects (osmotic type due to water flowing into intestine lumen). These effects depend on the individual physiologic state, alimentary bolus and its composition...... D. ental aspects
Mannitol is not fermented by the human buccal microflora. Thus, it is neither acidogenic nor cariogenic and these properties grant it a particular status in tooth decay prevention.
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P H Y S I C A L A N D C H E M I C A L P R O P E R T I E S ...... S. tability
Mannitol is remarkably stable: - it does not react with diluted acids, buffer solutions or amino groups. No Maillard reaction of the type: R-CHOH-CHO + R’-NH2 RCO-CH2-NHR’+ H2O - it does not undergo discoloration reaction at temperatures below 220°C or 240°C (depending on prevailing conditions)...... Solubility
Mannitol is soluble in different solvents Mannitol’s solubility in water at 20°C (part/part)*: ...... 40 ...... ➢ Water : 1 in 5.5 ...... 35 ...... 37,5 ...... l ...... o . ➢ Ethanol (95%) : 1 in 83 30 . . . . . 31 . . t ...... i ...... n ......
25 ...... n 25 ......
Ether : practically insoluble a . ➢ ......
20 ...... m ......
f 19 ...... o . ➢ Glycerin : 1 in 18 15 ......
. . . 15 ...... %
12.3 . 10 ...... ➢ Propanol-2 : 1 in 100 9.1 ...... 5 ...... ➢ Alkalis : soluble 0 0 10 20 30 40 50 60 70
A negative heat of solution is the origin Temperature (°C) of the cooling effect experienced after ingestion of mannitol powder (value of - 30 cal/g). . .
* From “Handbook of Pharmaceutical Excipients” Third Edition, . .
p. 325, A.H. Kibbe, Pharmaceutical Press, London, UK...... H. ygroscopicity
Due to its chemical properties and its Sorption Isotherms very high purity, Mannitol is non- ......
hygroscopic. Mannitol takes up water ...... t ......
c 90 ...... u
4. 0°C ...... d ...... o . only above relative humidities of 80 ...... r ...... p 20°C .
...... e 70 ...... h . 97% at 20°C and 40°C...... t ......
...... n
60 ...... i ......
...... r ...... e . 50 ...... t ...... a ...... w ......
40 ...... f ...... o ......
...... e . 30 ...... g ...... a ...... t ......
n 20 ...... e ...... c ...... r .
10 ...... e ...... P 0 050100
Relative humidity (%)
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P H Y S I C A L A N D C H E M I C A L P R O P E R T I E S ...... O. smolality
Mannitol can be used as therapeutic Mannitol Osmolality agent in order to increase diuresis in ...... concentrated solutions (15 % and ...... r . 1200 ...... e ...... t ...... a . 20 %); see values on the curve ...... w ......
. 1000 ...... g ...... hereafter. k ...... / ...... s . l ...... o ......
800 ...... m ...... s ...... o i ...... l ...... l ...... i 600 ...... m ......
...... f ...... o ......
......
400 ...... r ...... e ...... b ...... m ...... 200 ...... u ...... N ...... 0 0 20 40 60 80 100 120 140 160
Quantity g/kg water ...... C. rystalline forms Melting point
Mannitol is crystallised as the ß form and complies with the identification tests of different major Pharmacopoeias. Other crystalline forms (Ȋ and Ȏ) can be observed and differentiated by infrared spectrometry or by X ray diffraction. The melting range is the same for the 3 forms and lies between 165°C and 169°C.
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P H Y S I C A L A N D C H E M I C A L P R O P E R T I E S ...... Spectrometry
Infrared Mannitol - Ȋ - Infrared Spectrum absorption spectra (KBr) 100.0 Infrared absorption 80.0 n o i
spectrometry is an s
s 60.0 i m
identification method s n a
r 40.0 t
capable of detecting the crystalline polymorphism % 20.0 of tested products.
0.0 The spectrum of Mannitol 4000.0 3500.0 3000.0 2500.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 500.0 is typical of the ß form of Wave number/cm-1 mannitol. The spectrum of Mannitol - ß - Infrared Spectrum PEARLITOL SD mannitol shows it to be mainly in the 100.0 Ȋ form which is due to its
particular manufacturing 80.0
process. n o i
s 60.0 s i m
This form of mannitol can be s n a
r 40.0 transformed into the ß form t
after dissolution and % recrystallisation, as required 20.0
by the identification test in 0.0 mannitol monograph. 4000.0 3500.0 3000.0 2500.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 500.0 Wave number/cm-1
Mannitol - Ȏ - Infrared Spectrum
100.0
80.0 n o i
s 60.0 s i m s n a
r 40.0 t
%
20.0
0.0 4000.0 3500.0 3000.0 2500.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 500.0 Wave number/cm-1
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P H Y S I C A L A N D C H E M I C A L P R O P E R T I E S ......
NMR Spectra
Mannitol gives the following 1H and 13C Nuclear Magnetic Resonance (NMR) spectra:
Mannitol - 1H NMR Spectrum Mannitol - 13C NMR Spectrum
4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 79 78 77 76 75 78 79 80 4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 Deplacement chimique (Ȏ) em ppm Deplacement chimique (Ȏ) em ppm
The symmetry of the mannitol molecule leads to a simple three singlets 13C NMR spectrum.
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ...... P. EARLITOL® mannitol crystalline powders 3 grades of PEARLITOL mannitol crystalline powders
are available:
➢ PEARLITOL 160 C,
➢ PEARLITOL 50 C,
➢ PEARLITOL 25 C.
The high purity, stability
and non hygroscopicity
of PEARLITOL mannitol
crystalline powders mean
that they are the excipient of
choice for pharmaceutical
applications (granulation,
freeze-drying).
Characteristics
■ Particle size
Typical values of particle sizes of mannitol crystalline powders are given for guidance only (mean diameter, laser diffraction): ➢ PEARLITOL 160 C: 160 microns approx. ➢ PEARLITOL 50 C: 50 microns approx. ➢ PEARLITOL 25 C: 25 microns.
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ......
■ Rheology
PEARLITOL 160 C 50 C 25 C
Poured density (g/mL) 0.66 0.55 0.49 Tapped density (g/mL) 0.85 0.78 0.74 Ability to settle (mL) 25 46 60 Haussner ratio 1.29 1.42 1.51 Flowability (funnel; s) infinite infinite infinite Angle of repose (°) 47 50 50
These values are given for guidance only.
Applications
■ Dry forms
PEARLITOL mannitol crystalline powders are highly recommended for the manufacture of dry forms (granules, pellets, tablets) obtained by granulation. The different particle sizes, the non hygroscopicity, the absence of water and the stability give superior performances and improved productivity (ease of drying).
■ Freeze-drying
Mannitol is an interesting excipient for freeze-drying. Its solubility and hygroscopicity properties make it an excellent diluent in this application. Mannitol gives the freeze-dried material an aerated, light and porous structure and prevents it from collapse. Moreover, due to its polyol structure, mannitol acts as a cryoprotective agent.
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ...... P. EARLITOL® mannitol granular powders PEARLITOL DC and SD mannitol granular powders
has been especially designed
for direct compression
applications.
A range of different particle
sizes and densities of
PEARLITOL mannitol PEARLITOL DC
granular powders are available:
➢ PEARLITOL 100 SD,
➢ PEARLITOL 200 SD,
➢ PEARLITOL 300 DC,
➢ PEARLITOL 400 DC,
➢ PEARLITOL 500 DC.
PEARLITOL 200 SD PEARLITOL mannitol granular powders are free flowing and excellent diluent- binders for direct compression applications (fast dissolving tablets, chewable tablets…).
■ Rheology
PEARLITOL 100 SD 200 SD 300 DC 400 DC 500 DC
Poured density (g/mL) 0.48 0.45 0.62 0.68 0.64 Tapped density (g/mL) 0.57 0.52 0.69 0.76 0.72 Ability to settle (mL) 18 16 8 10 11 Haussner ratio 1.19 1.16 1.11 1.12 1.12 Flowability (funnel; s) 66788 Angle of repose (°) 39 38 39 37 39
These values are given for guidance only.
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ......
PEARLITOL mannitol granular powders offer all the required properties of a DC excipient: ➢ Excellent free flowing, ➢ Good compactibility with low friability, ➢ No sensitivity to tabletting speed, ➢ No lubricant sensitivity, ➢ Good dilution potential.
■ Compression property
PEARLITOL mannitol granular Compactibility of PEARLITOL powders give good hardness results on rotative FETTE P 1000 under industrial compression Compactibility ...... conditions. These results demonstrate ...... 140 ......
PEA. RLITOL ...... that PEARLITOL mannitol granular 120 ...... 200 SD ...... ) ...... N 100 ...... ( ...... powders are effective fillers and ...... PEARLITOL s ...... s ...... e 80 400 DC ...... n . binders for DC applications...... d . 60 ...... r ...... a ...... H . 40 ...... 20 ...... 0 20 25 30 35 40 45 50 55 60 65 70
Compression force (kN)
PEARLITOL 200 SD is a filler and Hardness variation as a function binder which is effective in various of the tabletting rotation speed conditions. It shows excellent ...... P. EAR. LITO. L 20. 0 SD...... 120 ......
performance even at high tabletting ...... ) . 100 ...... N . speed, allowing high productivity...... ( ......
...... s ......
80 ......
s 86 84 .
...... 82. e . . . . . 80...... n ...... d 60 ...... r ...... a ...... H 40 ...... 20 20000 50000 70000 100000
Rotation speed (tablets/H)
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ......
■ Lubrication sensitivity
PEARLITOL mannitol is tested in compression with magnesium stearate. It does not make any difference to the hardness of tablets even if the time taken to mix PEARLITOL mannitol and magnesium stearate varies from 2 to 30 minutes. This property ensures a certain reliability for the production.
Hardness profile as a function of the mixing time with lubricant
PEARLITOL 200 SD PEARLITOL 400 DC ......
3 ...... Mix: 2 min ...... 200 ...... ) ......
...... 2.5 ...... a ...... p ...... Mix: 30 min ...... ) ......
M Mix: 30 min ...... ( 2 ...... 150 ......
...... N ...... s ...... ( ......
...... s ...... Mix: 2 m. in s ...... e ...... s ...... 1.5 ...... n ...... e ...... d ...... n ...... 100 ...... r ...... d ...... a ...... r ......
. 1 ...... a ...... H ...... H ...... 50 ...... 0.5 ...... 0 ...... 0 2030 40 50 6070 8090 050100150200250300
Compression Force (kN) Compression pressure (Mpa)
■ Dilution potential
Formulations based on PEARLITOL mannitol are able to incorporate high proportions of non DC active substance.
Compression profile without and with ascorbic acid
PEARLITOL 200 SD PEARLITOL 400 DC ......
3 ...... 3.5 ...... ) ...... 0%...... 2,5 ...... a 3 0% ...... p ...... ) ...... a ...... M ...... 2.5 p ( ...... 2 ......
...... s ......
M 25% ...... s ...... ( ......
2 ......
. . . . e ...... s 1,5 ...... n ...... s ...... d ...... e ...... 1.5 ...... r ...... n ...... a ...... d ......
1 . . . . . 25% ...... r ...... H ...... 1 ...... a ...... H ...... 0,5 ...... 0.5 ...... 0 . . . 0 50 100 150 200 250 300 050100150200250300350400
Compression pressure (Mpa) Compression pressure (Mpa)
PEARLITOL 400 DC data was kindly provided by Pr K.J. Steffens, Institute of Pharmaceutical Technology, Bonn University, Germany.
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ......
PEARLITOL DC and SD mannitol granular powder are used in all types of tablets:
➢ fast dissolving tablets, ➢ chewable tablets, ➢ effervescent tablets, ➢ standard tablets.
Applications
■ Fast dissolving/chewable tablets
Below is an example of a formulation of a chewable/fast dissolving/dispersible tablet, containing taste masked dextromethorphan hydrobromide.
■ Preparation Taste Masked Dextromethorphan Dispersible Tablet
1. Mix for 5 minutes in a TURBULA (1) mixer Magnesium stearate PEARLITOL® 200 SD, Dextromethorphan HBr, 1.5% Sodium Starch Glycolate Dextromethorphan KLEPTOSE DC (betacyclodextrin) and Sodium 3.0% hydrobromide Starch Glycolate. 7.1% 2. Magnesium stearate is added and mixed for 5 minutes in the TURBULA (1) mixer.
3. Compression on a FROGERAIS (2) machine with 10 mm diameter flat bevelled punch. KLEPTOSE DC ➢ Tablet mass: 350 mg 42.9% ➢ Hardness: 48 N Disintegration time: 40 s ➢ PEARLITOL 200 SD 45.5%
(1) TURBULA: trademark of Willy A. Bachofen AG Maschinenfabrik, BASEL (Switzerland), (2) FROGERAIS: trademark of SVIAC/Schindler VITRY/SEINE (France).
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ......
■ Preparation Vitamin C effervescent tablets
In a LOEDIGE (4) mixer pour and mix Granulated tartaric acid Coated ascorbic acid 26.4% for 5 minutes in 6 steps: 20.0% 1. Tartaric acid and sodium bicarbonate, 2. Ascorbic acid and sodium ascorbate, 3. PEARLITOL® 200 SD, orange flavour and sodium saccharinate, XPEARLITOL 200 SD 4. Add a third of PEG 6000 9.4% and sodium benzoate in 3 steps. Sodium bicarbonate Granulated sodium ascorbate 30.8% 4.7% 5. Compression on EXACTA 21 (5) Sodium benzoate 3.7% machine with 20 mm flat bevelled punch PEG 6000 Sodium saccharinate 2.8% ➢ Tablet mass: 2.25 g 0.4% Orange flavour ➢ Hardness: 60 N 1.8% ➢ Disintegration time: around 1 minute
■ Preparation Antacid chewable tablets
Mixing steps in a TURBULA (1) mixer: PEARLITOL 200 SD 50,6% Aluminium hydroxide ➢ 10 mn for PEARLITOL 200 SD 22,2% and simethicone, ➢ 5 mn with hydroxides, flavor and sodium saccharinate, then sieving on 500 µm, ➢ 5 mn with stearate. Compression on a single press EXACTA 21 (5) with 16 mm diameter flat bevelled punch Magnesium hydroxide ➢ Tablet mass: 895 mg 22,2% ➢ Schleuniger hardness: 100 N Sodium saccharinate Simethicone 0.2% 2,8% Magnesium stearate Mint flavour 1.0% 1,0%
(1) TURBULA: trademark of Willy A. Bachofen AG Maschinenfabrik, BASEL (Switzerland), (4) LOEDIGE: trademark of Gebrüder Loedige Maschinenbau GmbH, PADERBORN (Germany) (5) EXACTA: trademark of FETTE: Wilhem Fette GmbH, SCHWARZENBEK, B. HAMBURG (Germany).
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F U N C T I O N A L P R O P E R T I E S A N D A P P L I C A T I O N S ......
■ Preparation Antacid chewable tablets Mixing steps in a TURBULA (1) mixer : PEARLITOL 400 DC 5 minutes for aluminium hydroxide, 72.4% magnesium hydroxide. Add the flavour and PEARLITOL 400 DC. Add the magnesium stearate and mix for 5 minutes. Compression on a FROGERAIS (3) machine with 13 mm diameter flat bevelled punch. ➢ Tablet mass: 800 mg Aluminium hydroxide 20.1% ➢ Thickness: 4.30 mm ➢ Schleuniger Hardness: 75 N Magnesium hydroxide Mint flavour 5.0% 1,0% Magnesium stearate 1.5%
Other applications
PEARLITOL 200 SD and 300 DC, 400 DC, 500 DC are recommended for applications in which flowability is of importance: hard capsule filling, sachets… PEARLITOL 300 DC, 400 DC and 500 DC can also be used as neutral carriers onto which active substances are poured or sprayed.
(1) TURBULA: trademark of Willy A. Bachofen AG Maschinenfabrik, BASEL (Switzerland), (3) FROGERAIS: trademark of SVIAC/Schindler VITRY/SEINE (France).
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P E A R L I T O L ® P F ......
Roquette has been Characteristics
manufacturing raw materials ■ Physical and chemical characteristics for the preparation of
injectable products for over PEARLITOL PF complies with the different existing 25 years. PEARLITOL PF monographs: mannitol pyrogen free grade ➢ European Pharmacopeia ➢ USP has been developed and ➢ Japanese Pharmacopeia introduced to the leading
companies, world-wide. ■ Biological and microbiological characteristics PEARLITOL PF Roquette performs endotoxins tests and pyrogenic is manufactured and substances detection on rabbits in its own controlled according to laboratories. These tests are carried out according to the recommendations of the various Pharmacopeia. the highest existing standards Due to our experience and total control of our production, Roquette is able to offer PEARLITOL PF and supplied throughout with the following specifications: the world. ➢ Endotoxin: 2.5 E.U./g maxi ➢ Total viable count: 100 col./g maxi ➢ Yeast: 10 col./g maxi ➢ Moulds: 10 col./g maxi
Applications
PEARLITOL PF is usually used in 5% and 10% solutions as a diuretic agent. It can be incorporated in complex solutions which may contain mineral salts. PEARLITOL PF is highly recommended for the manufacture of freeze-dried injectable preparations because of its cryoprotective effect, osmotic properties, physical stability, non hygroscopicity and excellent chemical inertness (no reaction with the amine function).
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P E A R L I T O L ® P A C K A G I N G ......
PEARLITOL mannitol packaging exists in various sizes and presentations:
Strippable Bag Cardboard Box Drum Paper + Polythene Polythene + Box Polythene + fibre drum 25 kg 25 kg 50 kg
PEARLITOL 160 C XX PEARLITOL 50 C XX PEARLITOL 25 C X PEARLITOL PF X
PEARLITOL 100 SD X (20 kg) PEARLITOL 200 SD X
PEARLITOL 300 DC X PEARLITOL 400 DC X PEARLITOL 500 DC X
I N T E R N A T I O N A L T E C H N I C A L S U P P O R T ......
At Roquette, a team of pharmacists and development scientists assisted by a dedicated application laboratory are at your disposal for further information and assistance regarding the use of Mannitol.
The information contained in this document is to the best of our knowledge true and accurate but all instructions, recommendations or suggestions are made without any guarantee. Since the conditions of use are beyond our control, we disclaim any liability for loss and/or damage suffered from use of these data or suggestions. Furthermore, no liability is accepted if use of any product in accordance with these data or suggestions infringes any patent. No part of this document may be reproduced by any process without our prior written permission.
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