content dear reader, - basfcontent no. 10, may 2003 excipients & actives for pharma imprint...

Content

No. 10, May 2003

Excipients & Actives for Pharma

Imprint

Trademarks are owned by BASF Aktiengesellschaft.

Ludipress® LCEA new direct compression excipient.K. Kolter, R. Heinz, B. Fussnegger

Kollidon® SR Sustained releaseformulations of different drugs.T. Steenpaß, T. C. Rock, K. Kolter

Kollicoat® EMM 30 DCoatings on pellets using fluidizedbed and Huettlin coaters.S. Scheiffele, K. Kolter, D. Kovacevic, G. Schepky

Kollicoat® IRBinding propertiesof the new polymer.K. Kolter

PresentationBASF Development PharmaIngredients.

NewsCaffeine may prevent skin cancer.

New MediaProducts for the food andpharmaceutical industry.

PreviewGastric resistance ofKollicoat® MAE 100 P.

Calendar

Contact

page 2–3

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page 8–9

page 10

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Publisher:BASF Aktiengesellschaft

Editorial staff:Dr. Volker Bühler, Valérie Filiatreau, Dr. Hubertus Folttmann, Dr. Bernhard Fussnegger, Dr. Karl Kolter, Dr. Jan-Peter Mittwollen, Dr. Anisul Quadir, Dr. Thorsten Schmeller, Silke Werth

Concept/Layout:MLW KommunikationsForm GmbH Werbeagentur, Mannheim

Print:Knopf druck + media, Edingen-Neckarhausen

Numerous drugs that are market-ed as solid oral dosage forms areavailable in many different poten-cies. The easiest way of producinga range of these is to developformulations using the cost-savingmethod of direct compressionprocessing. The Ludipress® rangecomprises excipients that satisfythe specific characteristics ofindividually tailored dosage forms.

Lozenges and effervescent tabletsmust dissolve quickly and shouldnot leave any residue. Ludipress®

LCE does not contain the disinte-grant Kollidon® CL; it is therefore

Dear Reader,

completely soluble in water andthus particularly suitable for thisapplication. Co-formulated withKollidon® CL as disintegrant,Ludipress® LCE also demonstratesits suitability for fast-disintegratingtablet formulations.

Since its introduction in 1999,Ludipress® LCE has found its wayinto various registered productsworldwide.

The article on pages 2 to 3 high-lights the properties of Ludipress®

LCE as an excipient for efficienttablet production.

Yours sincerely,

BASF AktiengesellschaftStrategic MarketingPharma Excipients

Bernhard Fussnegger


No. 10, May 2003 – page 2

particle size (laser diffraction),flowability (angle of repose andflow time with Pfrengle funnel),water sorption (sorption profile),amorphous lactose (differentialscanning calorimetry), granuleand surface structure (scanningelectron microscopy).

Tablet propertiesHardnessFriabilityStandard deviation of massContent uniformity(tablet dissolved in 0.1-N NaOH,filtered and measured at 300 nm).

TablettingLudipress® LCE tablets:Ludipress® LCE was blended withmagnesium stearate (0.5 %) for10 minutes and compressed atincreasing compression forces togive tablets of 10 mm diameterand 300 mg weight.

Glibenclamide tablets:Ludipress® LCE, glibenclamide(1.0 %, 0.5 %, 0.1 %), Kollidonmagnesium stearate (0.5 %) weresieved through 0.8 mm, blendedfor 10 minutes and compressedto give tablets of 8 mm diameterand 200 mg weight.

ResultsThe powder properties ofLudipress® LCE are summarized intable 1. The mean particle sizesdetermined by sieve analysis andlaser diffraction correspond toeach other. Both methods showa narrow particle size distribution.After drying at 105 ˚C most of thewater was bound as monohydrate,since the relative humidity of thepowder was comparably low andthe water sorption profile indicatednearly no water uptake up to 75 %r. h. This low water uptake in humidatmosphere led to the conclusion

29.5°

6.9 s

260 µm, slope n 1.85

275 µm, span 1.75

5.75 %

20.1 %

0.57 g/ml

1.19

-0.34 %

0.13 %

0.52 %

Angle of repose

Flow time (150 ml)

Mean particle size (sieve tower) d'

Mean particle size, D[4.3]

Loss on drying (105 ˚C)

Relative humidity

Bulk density

Hausner ratio

Water sorption 28 d/33 % r. h.

28 d/66 % r. h.

28 d/75 % r. h.

Content uniformity

Glibenclamide

2 mg/1 %

1 mg/0.5 %

0.2 mg/0.1 %

Average [%]

100.30

100.42

102.03

Weight

SD [%]

0.56

0.84

1.42

Content [%]

101.69

99.19

101.19

SD [%]

1.29

1.06

2.15

USP/Ph. Eur.

fulfilled

fulfilled

fulfilled

Ludipress® LCEA new direct compression excipient.K. Kolter, R. Heinz, B. Fussnegger

IntroductionLudipress® LCE, a new directcompression excipient based on96.5% lactose and 3.5% povidone(Kollidon® 30), is manufactured viaa special agglomeration processto achieve a compound with goodcompression properties connectedwith an excellent blending behavior.Direct compression of low doseddrugs is often prohibited due tosegregation of powder blends.Currently this remains a problemin the pharmaceutical industry [1].

ObjectiveThe objectives of this study were1. to characterize the new directcompression excipient Ludipress2. to correlate the powder proper-ties with the properties of tablets3. to check the suitability formanufacturing low dosed tablets.

Materials and MethodsMaterialsLudipress® LCE (BASF AG),glibenclamide micronized(Arzneimittelwerk Dresden),magnesium stearate (Bärlocher).

ApparatusKorsch PH 106 rotary press withcompression research system(Korsch Pressen GmbH), Turbulablender T2C (Bachofen AG).

Powder characteristicsParticle size (sieve tower withcalculation according to RRSB),

SEM-photo ofLudipress® LCE

(Figure 1)

Powder propertiesof Ludipress® LCE

(Table 1)

Properties ofglibenclamide tablets

(Table 2)


page 3 – No. 10, May 2003

Compression force-hardness profile ofLudipress® LCE(Figure 2)

Influence ofcompression speedon hardness ofglibenclamide tablets(Figure 3)

Photos of blends withcacao powder (10 %)(Figure 4)

Lactose

Ludipress® LCE

Content uniformity ofglibenclamide tablets(Figure 5)

that there is no amorphous lactosein this compound, which wassecured by DSC measurements.

Ludipress® LCE consists of porousgranules which are able to be de-formed under pressure. The com-pression force-hardness profile ex-hibits a nearly linear increase up to300 MPa equivalent to 25 kN for a10 mm tablet. Friability was zeroand the relative standard deviationof mass was between 0.4 and 0.7%.These excellent compression prop-erties can be explained by thefurrowed surface structure, whichcauses strong interlocking of thecompressed granules. Additionally,the effective binder povidone con-tributes to the hardness as it bindsthe fine lactose particles together(figure 2). If the compression speedis increased, most excipients pro-duced tablets with reduced hard-ness. This could not be detectedwith Ludipress® LCE. The hardnessof glibenclamide tablets remainedat the same level (figure 3).

Due to the furrowed surface struc-ture, Ludipress® LCE producesinteractive mixtures with active in-gredients, which do not segregate.This was visualized using fine ca-cao powder as colorant (10%) afterblending for 10 min. The differencein the blending behavior of Ludi-press® LCE and crystalline lactosecan be seen clearly (figure 4).

The suitability for dosage formswith a low drug dose was provenin glibenclamide tablets with acontent of 1.0 %, 0.5 % and 0.1 %active. All formulations fulfilled therequirements of USP and Ph. Eur.The standard deviation of contentuniformity was 0.3–0.8 % higherthan the standard deviation ofmass. This is an extremely posi-tive value, especially when thesimple blending process is takeninto consideration.

References[1] A. Armstrong, Pharm.Tech. Eur. 1997 (9), 24–30.

Conclusions Ludipress® LCE can be characterized as a direct compressionexcipient combining excellent flowability with outstandingblending and compression properties. Tablet properties like hardness, mass deviation and contentuniformity can be explained by the powder characteristicsespecially the granule and surface structure. Ludipress® LCE is especially suitable for the manufacturingof low dosed drugs by direct compression.

240

220

200

180

160

140

120

100

80

ha

rdn

ess

[N

]

250

200

150

100

50

090

6030 10

18

25

Glibenclamide 2.0 mg

Ludipress®

LCE 190.0 mg

Kollidon® CL 7.0 mg

Magnesiumstearate 1.0 mg

Tabletweight 200.0 mg

Diameter: 8 mm,flat, beveled edge

Fig. 3

2 mg (1.0 %) glibenclamide2.62.42.22.01.81.61.4

tablets0 1 2 3 4 5 6 7 8 9 10

0.260.240.220.200.180.160.14

0.2 mg (0.1 %) glibenclamide

co

nte

nt

[mg

]c

on

ten

t [m

g]

upperlimitsof USP

lowerlimitsof USP

upperlimitsof USP

Fig. 5 ■ Content – Average

lowerlimitsof USP

tabletting speed [Rpm]

compressionforce [kN]

Fig. 2compression force [kN]

Ludipress® LCE with0.5 % magnesium stearate

Tablet weight: 300 mgDiameter: 10 mm

0 5 10 15 20 25 30 35

ha

rdn

ess

[N

]


No. 10, May 2003 – page 4

Materials and MethodsMaterialsKollidon® SR (BASF AG);Tramadol-HCl (Chemagis Ltd.);Diltiazem-HCl (Farmacon);Diclofenac-Na (Irotec);Aerosil 200 (Degussa);Magnesium stearate (Bärlocher).

Powder propertiesMeasurement of angle of reposeand flow time with a Pfrenglefunnel.

TablettingBlending for 10 minutes in aturbula mixer, compressing byuse of an instrumented KorschEK0 single-punch press, tabletdiameter 10 mm, beveled edge.

Tablet propertiesDetermination with a Krämertablet tester (HT-TMB), friabilitywith an Erweka Friabilator.

Release studiesAccording to the USP XXIIImethod by use of a PharmatestPTW-S dissolution tester, 50 rpm,paddle, 37 °C, 0.08 N HCl (0–2 h),change to pH 6.8 phosphatebuffer (2–16 h); release study forthe diclofenac-Na formulation pH6.8 phosphate buffer (0–16 h);spectrophotometrical determina-tion of drug release.

Results and DiscussionFor all formulations a tablet hard-ness of roughly 200 N was aspiredin order not to falsify the drugrelease by an overdone tablethardness but to guarantee a goodmechanical tablet stability.As shown in table 1 the tramadolformulation shows excellent flowcharacteristics, easy tablet manu-facture and prominent mechanicaltablet properties. The drug disso-lution profile reaches approx. 90%after 16 h (figure 1).

Composition oftablets [mg] and

tablet characterisitics(Table 1)

IntroductionFrom an economical point ofview the production of sustainedrelease tablets by direct compres-sion is of great promise. An inno-vative excipient that offers goodcontrolled release characteristicstogether with excellent direct com-pression properties is required asthe essential tool for the develop-ment and manufacture of matrixtablets [1, 2].

ObjectiveIn this respect Kollidon® SR wasdeveloped as a free-flowing nonhygroscopic powder consistingof polyvinyl acetate (8 parts w/w)and polyvinylpyrrolidone (2 partsw/w). A convincing excipient isexpected to be easily applicablefor a broad selection of differentdrugs. In this study Kollidon® SR-based sustained release tabletssimilar to market products ofdifferent drugs are represented [3].

Kollidon® SRSustained release formulations of different drugs.T. Steenpaß, T. C. Rock, K. Kolter

DiclofenacK-SR(1:1.5)

DiclofenacK-SR(1:1)

DiltiazemK-SR(1:1.5)

TramadolK-SR(1:1.5)

Tramadol

Diltiazem

Diclofenac

Kollidon® SR

Aerosil 200

Magnesium stearate

Flow time [s]

Angle ofrepose [°]

Compressionforce [kN]

Hardness [N]

Friability [%]

100

–

–

150

2.5

1.25

9.2

24.6

12.6

211

< 0.01

–

120

–

180

3

1.5

15.5

29.0

7.96

217

0.01

–

–

100

100

3.4

3

20.9

26.6

7.88

195

0.09

–

–

100

150

3.4

3

21.5

26.1

7.02

229

0.07


page 5 – No. 10, May 2003

Release profile of aKollidon® SR-basedcontrolled releaseformulation ofdiltiazem-HCl(Figure 1)

■ Diltiazem 120 mgK-SR 180 mg

● Diltiazem 120 mgK-SR 180 mg/√t

Release profile of aKollidon® SR-basedcontrolled releaseformulation oftramadol-HCl(Figure 2)

■ Tramadol 100 mgK-SR 150 mg

● Tramadol 100 mgK-SR 150 mg/√t

Release profile of aKollidon® SR-basedcontrolled releaseformulation ofdiclofenac-Na(Figure 3)

▲ Diclofenac 100 mgK-SR 100 mg

● Diclofenac 100 mgK-SR 150 mg

■ Diclofenac 100 mgK-SR 100 mg/√t

◆ Diclofenac 100 mgK-SR 150 mg/√t

Conclusions Kollidon® SR can easily be applied for controlled releaseproperties by direct compression. It favors the development and manufacture of sustainedrelease tablets by its high dry binding capacity and the superbflow properties. This excipient offers a reliable sustained release characteristicindependent of the drug used.

The √t-charts (red lines) demons-trate good linearity for the releaseprofile.

Like the tramadol formulationKollidon® SR-based diltiazem tab-lets were also kept at a 1:1.5 ratio,which resulted in acceptable pow-der properties. The required tablethardness of 200 N has alreadybeen achieved with a compressionforce < 10 kN. The release behaviorof diltiazem (figure 2) depictsnearly the same image as it couldbe found for the tramadolformulation.

Although the angle of repose fora diclofenac-Kollidon® SR (1:1)composition is acceptable, theflow time reaches a critical limit.An increase of the Kollidon® SRadmixture up to 1:1.5 gives nosubstantial improvement of thepowder characteristics, but raisesthe mechanical performance.This 1:1.5 ratio is not sufficient tomask the known bad flow proper-ties of diclofenac, but consider-ably intensifies the sustainedrelease characteristic (figure 3).

The poor solubility of diclofenaccompared to the aforementioneddrugs explains the reduced re-lease rate while the Kollidon® SRratio is kept constant.

To modify the release profile, apartfrom varying the Kollidon® SR ratio,combinations together with otherexcipients are also practicable. Inno case any drug incompatibilityoccurred with Kollidon® SR-basedmatrix tablets.

References[1] M. J. Vasquez; Drug Dev.Ind. Pharm., 18; 1355, 1992.[2] U. Gundert-Remy, “Oralcontrolled release products”WVG, Stuttgart, 1990.[3] D. J. Chetty; Pharm.Tech. Eur. November, 1994.

0 2 4 6 8 10 12 14 16

100

80

60

40

20

0

time [h]

rele

ase

d d

rug

[%

]

0 0.5 1 1.5 2 2.5 3 3.5 4t1/2 [h]

0 2 4 6 8 10 12 14 16

100

80

60

40

20

0

time [h]

rele

ase

d d

rug

[%

]

0 0.5 1 1.5 2 2.5 3 3.5 4t1/2 [h]

0 2 4 6 8 10 12 14 16

100

80

60

40

20

0

time [h]

rele

ase

d d

rug

[%

]

0 0.5 1 1.5 2 2.5 3 3.5 4t1/2 [h]


No. 10, May 2003 – page 6

Results and DiscussionThe propranolol-HCl pelletscoated in a fluidized bed coaterdemonstrated very similar releasecharacteristics independently ofthe size of the batch.

As can be seen from figure 1, theretard pellets produced in a largebatch (MP 1) have a very slightlyslower release rate than the pelletsfrom the small batch (Strea 1) thatcan be explained by their more ho-mogeneous and even film coating.The reproducibility of the formu-lation used in the fluidized bedcoater is also very good, as canbe seen in figure 2.

Ibuprofen

60.00

37.50

2.50

–

100.00

Propranolol

30.00

46.70

2.50

20.80

100.00

Active

Avicel PH 101

Kollidon® VA 64

Granulac 230

Total

is added. Finally the homogenizedamount of pigment suspension(Kollidon® 30, Sicovit® Red 30,titanium dioxide, talc) is carefullystirred in (table 2).

Coating processThe coating was applied in afluidized bed coater (AeromaticStrea 1 and MP 1, Huettlin Kugel-coater HKC 5) on pellets (ibuprofen,propranolol-HCl) (table 3).

MethodsThe dissolution rates at differentcoating weights and the qualityof the coated pellets were deter-mined.

Ibuprofen

32.50

4.50

0.75

47.25

0.50

0.50

0.50

3.50

–

10.00

100.00

Propranolol

39.30

–

–

37.91

0.50

0.50

–

4.72

7.07

10.00

100.00

Kollicoat® EMM 30 D

Avicel PH 105

Pharmacoat 603

Water

Kollidon® 30

Sicovit® Red 30

Titanium dioxide

Talc

Pharsil 21046 VP

Water

Total

Ibuprofen

65 °C

41–42 °C

12 g/min

Propranolol

40–45 °C

28–30 °C

7–11 g/min

Inlet airtemperature

Outlet airtemperature

Spray rate

Kollicoat® EMM 30 DCoatings on pellets using fluidized bed and Huettlin coaters.S. Scheiffele, K. Kolter (BASF), D. Kovacevic, G. Schepky (Pharma Technology, 72488 Sigmaringen)

PurposeEthyl acrylate-methyl methacrylate(EMM) is a well-known polymerfor the manufacture of sustainedrelease dosage forms [1].Kollicoat® EMM 30 D exhibits acertain level of tackiness, whichlimits the coating process [2].This study describes trials in dif-ferent coaters and with differentbatch sizes.

MethodsMaterialsKollicoat® EMM 30 D, Sicovit® Red30, Kollidon® 30, Kollidon® VA 64(BASF AG), propranolol-HCl, ibu-profen (BASF AG), talc (Riedel deHaen), titanium dioxide (Kronos),Pharmacoat 603 (Shin-Etsu),Avicel PH 105/101 (Lehmann& Voss), Granulac (Meggle).

ApparatusCorundum disc mill (Fryma Maschi-nenbau GmbH), fluid bed coater(Aeromatic-Fielder, Huettlin),dissolution tester (PharmatestApparatebau), Spheronizer (HellerLabortechnik), sieve (Alexander),blender (Diosna).

Spray suspensionFirst the pore former (Avicel PH105, Pharmacoat 603) is dissolvedor suspended in the given amountof water. Then the calculatedamount of Kollicoat® EMM 30 D

Diagram of a Huettlincoater. Huettlin Kugel-

coater is a universal fluidbed unit suitable for

aqueous and organicprocesses such asdrying, granulation,

mixing, coating, micro-encapsulation and

layering, as well as hotmelt granulation and

coating.

Pellet formulations(Table 1)

Coating formulations (Table 2)

Process parameters (Table 3)


page 7 – No. 10, May 2003

Comparison of pelletssprayed in Aeromatictypes Strea 1 and MP 1(Figure 1)

■ MP 1● Strea 1

Reproducibility of thebatches produced inthe Aeromatic MP 1(Figure 2)

● MP 1_1■ MP 1_2▲ MP 1_3

Comparison of thepellets sprayed in theAeromatic type Strea 1and Huettlin coaters(Figure 3)

■ Huettlin● Strea 1

Effect of curing pelletscoated in the HuettlinKugelcoater(Figure 4)

■ with curing(40 ˚C/24 h)

● without curing

While the conventional fluidizedbed process can be scaled up with-out affecting the reproducibility ofthe formulations or the release rateof the pellets, considerable differ-ences are found in the pellets pro-duced in the Huettlin coater. Thedifference in film quality is clearlyvisible in figures 3 and 4. Thepellets produced in the Huettlincoater have a much smoother sur-face than the traditionally coatedpellets, which delay drug releasemore strongly (see figure 5).

Both the good reproducibility andthe small influence of subsequenttempering of the coated pellets canbe seen clearly from figure 6.The smooth film obtained in thiscoating process makes it unnec-essary to temper the pelletsafterwards.

References[1] T. C. Rock , D. Flick,K. Kolter, Proc. of the 27thInternational Symposium onControlled Release of Bio-active Materials, Paris, 7–13July 2000, 8406.[2] H. Erdmann, S. Scheiffele,G. Schepky and K. Kolter,Proc. of the 3rd WorldMeeting APV/APGI, Berlin,3–6 April 2000, p. 131.

Conclusions The formulations testeddemonstrate good repro-ducibility both in the con-ventional fluidized bedcoater and in the HuettlinKugelcoater. The fluidized bed processcan be scaled up withoutmuch effect on the filmquality and the release rate. The Huettlin Kugelcoatergives more homogeneousfilmcoatings and slowerrelease rates than fluidizedbed machines. It is not necessary totemper the coated pellets.

0 4 8 12 16 20 24

100

80

60

40

20

0

time [h]

rele

ase

d d

rug

[%

]

Medium: 0–2h: 0.08 N HCl,2–24 h: buffer pH 6.8,propranolol-HCl pellets,coating weight: 3.3 mg/cm3,Strea 1: 500 g, MP 1:1 kg

0 4 8 12 16 20

100

80

60

40

20

0

time [h]

rele

ase

d d

rug

[%

]

Medium: 0–2 h: 0.08 N HCl,2–24 h: buffer pH 7.2ibuprofen pellets,coating weight: 4 mg/cm3

0 4 8 12 16 20

100

80

60

40

20

0

time [h]

rele

ase

d d

rug

[%

]

Medium: 0–2 h: 0.08 N HCl,2–24 h: buffer pH 7.2ibuprofen pellets,coating weight: 4 mg/cm3

0 4 8 12 16 20 24

100

80

60

40

20

0

time [h]

rele

ase

d d

rug

[%

]

Medium: 0–2 h: 0.08 N HCl,2–24 h: buffer pH 6.8propranolol-HCl pellets,coating weight: 3.3 mg/cm3


No. 10, May 2003 – page 8

ResultsThe granulation efficiency can bedemonstrated explicitly by meansof the mean particle size and flowbehavior. All binders tested,Kollicoat® IR, Kollidon® VA 64 andHPMC 3 mPas, greatly increasedthe mean particle size from 67resp. 92 µm of the ungranulatedpowder blend to 483–545 resp.355–398 µm in mixer granulation.Simultaneously angle of reposedecreased from 49.7° resp. 40.0°to 31.9–34.0° and the non-flowingpowder was transformed into free-

Kollicoat® IRBinding properties of the new polymer.K. Kolter

PurposeKollicoat® IR (polyvinyl alcoholpolyethylene glycol graft copoly-mer) was designed as an instantrelease film-forming agent. In prin--ciple, water-soluble polymers canact as wet binders in tablet manu-facturing. The aim of this study wasto investigate and assess its wetbinding properties by comparisonwith well-known binders.

MethodsMaterialsPolyvinyl alcohol-polyethyleneglycol graft copolymer (Kollicoat®

IR, BASF Aktiengesellschaft),copovidone (Kollidon® VA 64,BASF Aktiengesellschaft), HPMC3 mPas (Pharmacoat 603, Shin-Etsu), ascorbic acid powder (BASFAktiengesellschaft), corn starch(C-Pharm, Cerestar), lactose(Sachelac 80, Meggle), micro-crystalline cellulose (Avicel PH 101,FMC), crospovidone (Kollidon® CL,BASF Aktiengesellschaft),magnesium stearate (Bärlocher).

MethodsKollicoat® IR, Kollidon® VA 64 andHPMC 3 mPas were tested in twoformulations, both at a binderlevel of 3 %.The tablets were compressed ona Korsch PH 106 rotary pressequipped with Compression Re-search System at 10, 18 and 25 kN.

flowing granules. Agglomerationwas also apparent in fluid bedgranulation. However, as expected,particle size in fluid bed granula-tion (148–189 µm) was lower whencompared to granulation in amixer, and angle of repose slightlyhigher due to an increased poros-ity and rougher surface structure(figure 1). Both, in mixer and fluidbed granulation, Kollicoat® IRshowed excellent agglomerationactivity comparable to the well-known binders Kollidon® VA 64and HPMC 3 mPas.

Placebo powder blend

Placebo granulesKollicoat® IR

Settings of fluid bed granulation

Concentration binder solution:Inlet air temperature:Spray rate:Outlet air temperature:Granulation time:

Settings of mixer granulation

Concentration binder solution:Propeller speed:Granulation time:Sieve size:

(Glatt GPC G3)

7.550 °C30 g/minapprox. 27 °Capprox. 20 min

(Stephan mixer)

15 %800 rpm12 mm0.8 mm

Table 3: Peroxide formation of Kollicoat® IR

storage time

0 months3 months3 months6 months6 months

12 months12 months18 months18 months

storage conditions

–25 °C/60 % r. h.40 °C/75 % r. h.25 °C/60 % r. h.40 °C/75 % r. h.25 °C/60 % r. h.40 °C/75 % r. h.25 °C/60 % r. h.40 °C/75 % r. h.

peroxide level (meq/kg)

1< 1< 1< 1< 14131

Loss on drying

Angle ofrepose

Flow time

Mean particlesize(D[4,3]-value)

Bulk density

Powder blend

–

49.7°

blocking

67 µm

0.57 g/ml

Kollicoat® IR

6.6 %

32.4°

8.9 sec

545 µm

0.47 g/ml

Kollidon® VA 64

6.8 %

34.0°

8.7 sec

497 µm

0.48 g/ml

HPMC 3 mPas

7.1 %

33.9°

8.7 sec

483 µm

0.50 g/ml

Table 2: Powder characteristics of placebo granules

Placebo tablets

–230.0 mg230.0 mg

–15.0 mg22.5 mg2.5 mg

500.0 mg12 mm1.50 kg

Ascorbic acid tablets

50.0 mg–

130.0 mg130.0 mg10.0 mg10.0 mg2.0 mg

332.0 mg10 mm1.33 kg

Ascorbic acidCorn starchLactoseMCCBinderKollidon® CLMagnesium stearate

TotalDiameterBatch size

Table 1: Tablet formulations


page 9 – No. 10, May 2003

Conclusions Kollicoat® IR exhibited excellent binding properties in wet granulation (mixer and fluid bed). As a binder Kollicoat® IR is characterized by ● good flowability of the granules● high tablet hardness ● low ejection forces ● short disintegration times. Due to the low peroxide level it is highly suitable for low dosed and oxygen sensitive drugs.

Particle size distributionof placebo granules(Figure 1)

Hardness-compressionforce profile ofplacebo tablets(mixer granulation)(Figure 2)

Hardness-compressionforce profile of ascorbicacid tablets(Figure 3)

Ejection forces ofascorbic acid tablets(fluid bed granulation)(Figure 4)

Disintegration ofplacebo tablets(Figure 5)

The formation of granules is pro-moted by the excellent film-formingproperties of the polymers. A bindershould not only improve the flowproperties but also improve com-pressibility and tablet properties.The hardness-compression forceprofiles clearly indicate that allbinders tested have good bindingpower. Kollicoat® IR was particu-larly effective in mixer granulationof ascorbic acid tablets, where itoutperformed Kollidon® VA 64and HPMC 3 mPas (73 to 59 and63 N at 18 kN compression force).However, in the placebo tabletsKollidon® VA 64 resulted in slightlyharder tablets (figure 2 and 3).A comparison of the ejection forcesof fluid bed granulated ascorbicacid tablets revealed lower valuesfor Kollicoat® IR. Thus, this polymerpromotes the lubrication effect ofmagnesium stearate (figure 4).The disintegration times of thetablets are correlated with the dis-solution speed and viscosity of thebinders used. Whereas Kollicoat®

IR and Kollidon® VA 64 showed alow viscosity of 115 mPas and 49mPas in a 20% solution and there-fore short disintegration times of1–2 min, HPMC even in the lowestviscosity grade (800 mPas/20 %solution) prolonged disintegrationup to 3–4 min (figure 5). A binderparticularly for low dosed and oxy-gen sensitive drugs should initiallyhave a low peroxide content andshould not generate peroxidesupon storage. The peroxide levelsof Kollicoat® IR remained very loweven after 18 months at 40 °C/70%r. h. In order to show that there isno binder-related degradation ofascorbic acid a stability study wasinitiated.

Loss on dryingAngle of reposeFlow timeMean particlesize (D[4,3]-value)Bulk density

3.1 %35.4°

7.8 sec

189 µm

0.34 g/ml

Powderblend

–40°

blocking

92 µm

0.45 g/ml

3.0 %32.6°

8.2 sec

397 µm

0.57 g/ml

2.7 %34.3°

7.8 sec

162 µm

0.43 g/ml

2.3 %31.9°

7.4 sec

355 µm

0.57 g/ml

2.9 %35.8°

8.2 sec

148 µm

0.43 g/ml

2.2 %32.2°

8.6 sec

398 µm

0.57 g/ml

Kollicoat® IR mixer fluid bed

Kollidon® VA 64 mixer fluid bed

HPMC 3 mPas mixer fluid bed

Table 4: Powder characteristics of ascorbic acid granules

0 5 10 15 20 25 30

80

60

40

20

0

compression force [kN]h

ard

ne

ss [

N]

Fig. 2

● Kollicoat® IR■ Kollidon® VA 64▲ HPMC 3 mPas

0 5 10 15 20 25 30

180

160

140

120

100

80

60

40

20

0

compression force [kN]

eje

cti

on

fo

rce

[N

]

Fig. 4

● Kollicoat® IR■ Kollidon® VA 64▲ HPMC 3 mPas

0 5 10 15 20 25 30

80

60

40

20

0

compression force [kN]

ha

rdn

ess

[N

]

Fig. 3

● Kollicoat® IR mixer gran.■ Kollidon® VA 64 mixer gran.▲ HPMC 3 mPas mixer gran.● Kollicoat® fluid bed gran.■ Kollidon® VA 64 fluid bed gran.▲ HPMC 3 mPas fluid bed gran.

0 10 100 1000 10000

16

14

12

10

8

6

4

2

0

particle diameter [µm]

volu

me

[%

]

Fig. 1

● Kollicoat® IR■ Kollidon® VA 64▲ HPMC 3 mPas● Powder Blend

4:00

3:00

2:00

1:00

0:00

dis

inte

gra

tio

n t

ime

[m

in:s

ec

]

10.5 kN 16.9 kN 24.2 kNKollicoat® IR

10.2 kN 17.9 kN 26.6 kNKollidon® VA 64

10.2 kN 17.3 kN 24.9 kNHPMC 3 mPasFig. 5

1:23

1:56

1:15 1:06

2:03

1:21

2:45

3:353:10


No. 10, May 2003 – page 10

just like a pharmaceutical develop-ment department, with modernmachinery that is suitable for run-ning all the processes of a state-of-the-art drug manufacturingplant. Additionally, we utilize thecapabilities of BASF in terms ofanalytics and physico-chemicalcharacterization. However, the keyfactor to success is our personneland we heavily rely on motivated,knowledgeable and well-trainedstaff.

We will continue to work hardin order to develop new pharma-ceutical excipients and activeformulations to provide you witheven more tools for new drugdelivery systems.

BASF – Innovation in PharmaIngredients

Furthermore, numerous newproducts are in our R&D pipeline.Of course, improvement of ourexisting products is an ongoingobjective. This applies both toexcipients and actives, where weare looking for new formulationswith attractive benefits.

Our pharma ingredients lab is notonly responsible for developmentissues but also for application tech-nology. We continuously try to findnew applications for our excipients,develop and optimize drug formu-lations, optimize pharmaceuticalmanufacturing processes andsolve any problems you may en-counter. With these activities weaim to serve you in an optimalmanner.

In order to optimize coordinationwith you, our facility is equipped

PresentationBASF Development Pharma Ingredients.T. Steenpaß, T. C. Rock, K. Kolter

You are probably familiar with thisfamous rhetorical question of A.T.Florence, which expresses the factthat new excipients are relativelyrare. Despite the fact that thedevelopment of a new excipient isa very time- and cost-consumingprocess, BASF has establishedthe strategy of differentiating itselffrom competitors by continuouslydeveloping new excipients andactive formulations. These newmaterials offer pharmaceuticalcompanies opportunities for new,innovative drug delivery systems.Furthermore, drug quality andsafety are enhanced.

Since 1996, the following productshave been launched: Kollicoat®

MAE 30 DP, Kollicoat® MAE 100 P,Kollicoat® EMM 30 D, Ludipress®

LCE, Kollidon® SR, Kollicoat® SR30 D and Kollicoat® IR.

Pharma Ingredientsdevelopment group


page 11 – No. 10, May 2003

Caffeine molecule

It covers all the maintechnical data on BASFvitamins, carotenoidsand other nutritionalingredients for thepharmaceutical andfood industries and canbe ordered with theattached reply card.

New MediaProducts for the food and pharmaceutical industry.

NewsCaffeine may prevent skin cancer.

Technical InformationBASF has been involved in thefield of health and nutrition forsome 20 years. During this timewe have developed to become animportant partner to the pharma-ceutical and food industries.Today, BASF offers a wide rangeof high-quality products and ser-vices worldwide in the areas ofhealth and nutrition.

Our extensive product range com-prises vitamins, vitamin blends inoil and in powder form and carot-enoids, but also polyunsaturatedfatty acids, colorants and numer-ous other specialties. This book/CD ROM is intended to meet theneeds of our customers for a com-prehensive, up-to-date handbookwith a clear layout providing quickaccess to information.

Treating the skin with caffeine hasbeen shown to prevent skin cancerin laboratory studies conducted atthe Susan Lehman Cullman Labo-ratory for Cancer Research atRutgers, The State University ofNew Jersey.

It has been known for some timethat skin cancer is caused predo-minantly by sunlight. The authors,a group that included Conney anda team of other researchers in thelaboratory, explained that the useof sunscreens has resulted in a de-crease of the risk of skin cancers,but that there is a need to identifyadditional approaches for skin-cancer prevention in individualspreviously exposed to high levelsof sunlight.

The research team, all membersof the school's Department ofChemical Biology, studied a specialstrain of hairless mice that hadbeen exposed to ultraviolet B

radiation twice weekly for 20weeks. This put the mice at riskfor tumor formation and skin cancer.Subsequent to exposure, the re-searchers applied caffeine andepigallocatechin gallate (EGCG),two of the components of greentea, topically to the skin. Both caf-feine and EGCG significantly inhib-ited cancer formation in the mice.

Although the study showed thatmost of the positive effects weretrue for both of these substances,caffeine has an advantage overEGCG: EGCG is chemically lessstable; thus, there could be aproblem in applying it topically.Conney said that a previous studyconducted in the laboratory dealtwith caffeine taken orally.The caffeine was provided in thedrinking fluid for the mice and theresearchers found that it inhibitedultraviolet radiation-inducedtumors and cancers in this caseas well.

Conney cites the advantages ofusing direct skin application overoral administration, pointing to theability to administer more highlyconcentrated and larger overalldosages. “Whether you can giveenough orally to be effective in hu-mans is not known”, said Conney.“And whether people could ingestthe necessary amount without be-coming hyperactive is also a realquestion mark.” The publishedstudy also reported the highly se-lective action of both caffeine andEGCG in destroying cancer cells.Adjacent normal skin cells werenot affected. “The discovery of thisselectivity was very exciting”, saidConney. “Also, in our study, it didn’tmatter whether the tumors werebenign or malignant; cells of bothtypes were destroyed whilst normalcells remained unaffected.” Thestudy suggests further research isneeded to determine whether or nottopical application of these agentswould be effective in humans.


page 12 – No. 10, May 2003

AsiaBASF Asia PacificRegional HQPharma Solutions,Dr. Danilo MercadoBASF SouthEast Asia Pte Ltd9/F., Suntec Tower Three7 Temasek BoulevardSingaporeFax: +65/430 9812

EuropeBASF AktiengesellschaftMEE/HP-Rheincenter,Mr. Peter HoffmannD-67056 LudwigshafenGermanyFax: +49/621 60 76940

NAFTABASF CorporationPharma Solutions,Mr. Patrick Glaser3000 Continental Drive-NorthMount Olive, NJ 07828-1234USAFax: +1/973 426 5355

South AmericaBASF S.A.Human Fine Chemicals,Mr. Giancarlo Farias MarinhoEstrada SamuelAizemberg, 170709851-550 São Bernardodo Campo – SPBrazilFax: +55/11 43 43 22 55

Or visit our website: www.pharma-solutions.basf.com

Please contact your local BASF subsidiaryor one of the following regional centres:

Contact

18th to 23rd July, 2003

30th International Symposium onControlled Release of Bioactive MaterialsGlasgow, Scotland

27th to 29th October, 2003CPhI WorldwideFrankfurt*, Germany

23rd to 30th October, 2003AAPS (American Association ofPharmaceutical Scientists) Annual MeetingSalt Lake City*, USA

4th to 9th September, 2003World Congress of Pharmacy and Pharmaceutical Sciences, 63rd Congress of FIPSydney, Australia

26th to 28th September, 20035th Central European Symposium onPharmaceutical Technology and BiotechnologyLjubljana, Slovenia

29th May to 3rd June, 2004Pharmaceutical Sciences World Congress (PSWC2004)Kyoto, Japan

Summer 200431st International Symposium on Controlled Release of Bioactive MaterialsOrlando*, USA

* BASF will be represented.

Calendar

Kollicoat® MAE 100 P is a redis-persible powder of methacrylicacid copolymer type C which ismanufactured by spray-drying therespective dispersion marketedas Kollicoat® MAE 30 DP.The major advantage of Kollicoat®

MAE 100 P compared to otherproducts is that neutralization

with sodium hydroxide is notnecessary as it is already partlyneutralized.

ExAct No. 11 will include sampleformulations and a comparison ofthe two Kollicoat® MAE gradesregarding their gastric resistance,spraying behavior and viscosity.

PreviewGastric resistance of Kollicoat® MAE 100 P.

Should you require informationin advance, please contact yourlocal BASF subsidiary or one ofour regional marketing offices.

For technical reasons, the article onKollicoat® SR 30 D which was announcedin ExAct No. 9 could not yet be published.This article will appear in one of the forth-coming editions.

Pleaseapply

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BASFAktiengesellschaftMEM/PE – D 205Attn: Dr. Hubertus Folttmann67056 Ludwigshafen


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Please send me the following information:

■ “Generic Drug Formulations”ringfile with 600 drug formulations.

■ “Kollidon® – Polyvinylpyrrolidone forthe pharmaceutical industry” (book).

■ “Functions and Applicationsof BASF Pharma Excipients”“Generic Drug Formulations”and “Kollidon®” (CD-ROM)

■ “Functions and Applications of BASFPharmaceutical Excipients” (booklet)

■ CD-ROM on Contract Manufacturing.

■

■ Technical Informationon Ludipress® LCE.

■ Technical Informationon Kollidon® SR.

■ Technical Informationon Kollicoat® EMM 30 D.

■ Technical Informationon Kollicoat® IR.

■ Products for the Food andPharmaceutical Industry –Technical Information (book).

■ Products for the Food andPharmaceutical Industry –Technical Information (CD-ROM).

■ I would like to receive ExActin future.

Please send me the following information:

■ “Generic Drug Formulations”ringfile with 600 drug formulations.

■ “Kollidon® – Polyvinylpyrrolidone forthe pharmaceutical industry” (book).

■ “Functions and Applicationsof BASF Pharma Excipients”“Generic Drug Formulations”and “Kollidon®” (CD-ROM)

■ “Functions and Applications of BASFPharmaceutical Excipients” (booklet)

■ CD-ROM on Contract Manufacturing.

■

■ Technical Informationon Ludipress® LCE.

■ Technical Informationon Kollidon® SR.

■ Technical Informationon Kollicoat® EMM 30 D.

■ Technical Informationon Kollicoat® IR.

■ Products for the Food andPharmaceutical Industry –Technical Information (book).

■ Products for the Food andPharmaceutical Industry –Technical Information (CD-ROM).

■ I would like to receive ExActin future.

content dear reader, - basfcontent no. 10, may 2003 excipients & actives for pharma imprint...

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