Content Dear Reader, · Dear Reader, pean Pharmacopoeia under the monograph name “Macrogol 15 hydroxystearate”. Beside the outstanding toxicologi-cal characteristics like a low

Content

No. 11, October 2003

Excipients & Actives for Pharma

Imprint

Trademarks are owned by BASF Aktiengesellschaft.

Kollicoat® SR 30 DCoated drug delivery systems.K. Kolter, S. Gebert

Kollicoat® MAE 100 PA redispersible powder of methacrylicacid copolymer type C.S. Scheiffele, H. Ascherl, F. Ruchatz and K. Kolter

Kollidon® SRCompression behavior.K. Kolter

Solutol® HS 15Practical aspects for theproduction of solubilizates.K. Kolter, F. Ruchatz

News A new multipurpose plant

at Minden site.

Solutol® HS 15 monographed.

New MediaProducts for the food andpharmaceutical industry.

PreviewSustained release floating systemsbased on Kollidon® SR.

Calendar

Contact

page 2–3

page 4–5

page 6–7

page 8–9

page 10

page 11

page 11

page 12

page 12

page 12

Publisher:BASF Aktiengesellschaft

Editorial staff: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

High throughput screening in thedevelopment of new drugs leads tocompounds with higher molecularweight and mostly poor water sol-ubility. The latest developments inthe pharmaceutical industry showthat a dramatic 41% of New Chem-ical Entity developments fail dueto poor bio-pharmaceuticalproperties.

Solutol® HS 15, a solubilizer devel-oped by BASF, meets the require-ments of an effective modernsolubilizer and is approved forparenteral applications. It has justbeen monographed in the Euro-

Dear Reader,

pean Pharmacopoeia under themonograph name “Macrogol 15hydroxystearate”.

Beside the outstanding toxicologi-cal characteristics like a low his-tamine release compared to othersolubilizers also the good solubi-lizing capacity and the possibilityto sterilize solutions with Solutol®

HS 15 make it an excipient ofchoice for your formulation devel-opment. An article in this issue ofExAct is addressing some practicalaspects for the production ofsolubilizates with Solutol® HS 15.

Yours sincerely,

BASF AktiengesellschaftStrategic MarketingPharma Excipients

Dr. Thorsten Schmeller


No. 11, October 2003 – page 2

subjected to a friability test (500revolutions, drop height 15.5 cm)in an Erweka Friabilator, allowedto fall 20 times from a height of1.5 m, and pricked with a needle.

Results and DiscussionFrom theoretical considerations,it is clear that a controlled releasecoating on a tablet must possessa high degree of flexibility, to en-sure that any swelling of the core– whether in storage or during drugrelease – does not crack the film.It was found in tests on isolatedfilms that polyvinyl acetate (Kolli-coat® SR 30 D) has far greaterelasticity than ethyl cellulose orammonio methacrylate copolymer.

The permeability of the film coatingcan be adjusted by adding water-soluble or water-swellable sub-stances, polymers if possible. Asis to be expected, the release rateslows with increasing thickness ofthe coating. The release curve isS-shaped, as, initially, water hasto penetrate the coating and enterthe core in order to at least par-

Kollicoat® SR 30 DCoated drug delivery systems.K. Kolter, S. Gebert

IntroductionSustained release dosage formsinclude single-unit and multiple-unit forms as well as coated formsand matrix forms [1]. Up to now,with the exception of the OROSSystem [2], the production of coat-ed single-unit forms has been re-garded as a malpractice, as the riskof dose dumping due to an incor-rectly applied coating, or damageto a coating was too high. TheOROS System is used in severalproducts that are available on themarket, but it has major disadvan-tages, such as the tricky operationof laser drilling, the use of organicsolvents, high cost, and a low con-centration of the drug in the core.

ObjectiveThe aim of this project was to de-velop a coated, sustained releasesingle-unit form that is simple tomanufacture and poses no risk ofdose dumping.

ExperimentalMaterialsKollicoat® SR 30 D (polyvinyl ace-tate dispersion, BASF Aktienge-sellschaft), metoprolol tartrate(Moehs S. A.).

MethodsMetoprolol tartrate was granulatedwith Kollidon® 30 solution, mixedwith the other excipients for 10minutes in a Turbula mixer, andcompressed into tablets on aKorsch PH 106.

Tablet cores in batches of 5.0 kgwere spray-coated with a pig-mented Kollicoat® SR 30 D disper-sion in a 24" Accela Cota.

Mechanical testing of the tabletsThe film-coated tablets were

tially dissolve the drug substancebefore this can diffuse out throughthe coating. The time lag betweenfirst contact with water and drugrelease also depends on thethickness of the coating and thequantity of water-solubleexcipients.

The coated tablets were subjectedto strong mechanical stress.

Table 2:Coating composition

Kollicoat®

SR 30 D 43.5 %

Triacetin 0.7 %

Kollicoat® IR 3.3 %

Kollidon® 30 0.5 %

Titaniumdioxide 0.5 %

Sicovit® Red(iron oxide),optional 0.5 %

Talc 3.5 %

Water 47.5 %

100.0 %

Table 3:Coating parameters

Batch size 5.0 kg

Inlet airtemperature 50 °C

Producttemperature 35 °C

Atomizingpressure 2.0 bar

Spraying rate 22 g/min

Coatingweight 4, 6, 8, 10 mg/cm2

Table 1:Core composition

Metoprololtartrate 200.0 mg

Kollidon® 30 6.0 mg

Di-Tab 160.0 mg

Aerosil 200 3.0 mg

Talc 4.0 mg

Magnesiumstearate 4.0 mg

Total tabletweight 391.5 mg


page 3 – No. 11, October 2003

300

250

200

150

100

50

0

elo

ngat

ion

at b

reak

[%

]

Kollicoat®

SR 30 DEthocel

FP7Ammonio

methacrylatecopolymer

AquacoatECD

Elongation at breakof various coatings(Figure 1)

■ with 5 % triacetin■ with 10 %propylene glycol

Drug release ofmetoprolol tablets as afunction of coatingthickness(Figure 2)

■ cores● 4 mg/cm2 coating

6 mg/cm2 coating■ 8 mg/cm2 coating● 10 mg/cm2 coating

Influence of mechanicalstress on drug releaseof metoprolol tablets(Figure 3)

punctured■ friability test● untreated

Neither a friability test (500 revo-lutions, 15.5 cm drop height) nor20 drops from a height of 1.5 mhad any noticeable effect on therelease characteristics.Surprisingly, the film-coated tab-lets can even be pricked with aneedle without affecting drugrelease. Kollidon® SR possessesenormous plasticity that ensuresthat small holes are self-sealing,particularly when the tablet is in-troduced into an aqueous medium.As a result, such coatings have apreviously unknown self-repairmechanism.

References[1] M.N.V. Ravi Kumarand N. Kumar, Polymericcontrolled drug deliverysystems, Drug Dev. Ind.Pharm. 27, 1–30 (2001).[2] S. Kettelhoit et al.,Osmotic drug deliverysystem, German PatentApplication 19747261,(1999).

Conclusions Film coatings based onKollicoat® SR 30 D are veryresistant to mechanicalstress and possess a self-repair mechanism. The release rate can beadjusted by using water-soluble polymers and byvarying the coating thickness. Film coatings based onKollicoat® SR 30 D allowthe simple manufacture ofcoated controlled releasesingle-unit forms withoutthe risk of dose dumping.

0 h 1.5 h 3.5 h 4.5 h 8 h 16 h

188

300

5.4 5.7 3.0 1.5 < 2.0% < 2.0%

23 °C/54 % r. h.

0 4 8 12 16 20 24time [h]

dru

g r

ele

ase

[%

]

120

100

80

60

40

20

0

Medium: 0.08 N HCl (0–2 h),phosphate buffer 6.8 (2–24 h),50 rpm

0 4 8 12 16 20time [h]

dru

g r

ele

ase

[%

]

120

100

80

60

40

20

0

Medium: 0.08 N HCl (0–2 h),phosphate buffer 6.8 (2–24 h),50 rpm



IntroductionKollicoat® MAE 100 P is a non-dusting redispersible powder gradeof Kollicoat® MAE 30 DP (meth-acrylic acid copolymer type C) forenteric coating. It is not necessaryto add NaOH to redisperse thisproduct, since it is already partlyneutralized.

PurposeThe objective of this study wasto investigate the enteric coatingproperties of the product and tocompare them with those of thedispersion.

MethodsMaterialsMethacrylic acid ethyl acrylatecopolymer (Kollicoat® MAE 30 DP;Kollicoat® MAE 100 P); Sicovit®

Red 30; titanium dioxide; propyleneglycol, BASF Aktiengesellschaft;

talc, Riedel de Häen; triethylcitrate, Merck.

ApparatusAccela Cota 24" (Manesty Ma-chines Ltd.), dissolution apparatus(PTW-S, Pharmatest Apparate-bau), straight-arm paddle agitator.

Composition and preparationof propranolol-HCl coresPropranolol-HCl 40 mg (KnollAktiengesellschaft), Ludipress®

97.5 mg (BASF Aktiengesellschaft),Avicel PH 102 97.5 mg (FMC),Kollidon® VA 64 12.5 mg (BASFAktiengesellschaft), magnesiumstearate 2.5 mg (Bärlocher).The ingredients of the formulationwere mixed in a Diosna mixer andcompressed with a force of 15 kNinto cores with the following pa-rameters: 9 mm diameter, 12 mmradius of curvature, 250 mg weight.

Composition and preparationof the spray dispersion Pigment dispersionTo prepare the pigment dispersionSicovit® Red 30, titanium dioxideand talc were intensively stirred inand homogenized using a disc mill.

Polymer dispersionKollicoat® MAE 30 DP:Propylene glycol or triethyl citratewas mixed with water and thenKollicoat® MAE 30 DP was addedunder stirring.Kollicoat® MAE 100 P:The powder was introduced intothe water with stirring. After redis-persal was complete (about 3 h)the plasticizer was stirred in.

Spray suspension (table 1)The pigment dispersion wasmixed under stirring into thepolymer dispersion.

Spray suspension(Table 1)

Kollicoat® MAE 100 PA redispersible powder of methacrylic acid copolymer type C.S. Scheiffele, H. Ascherl, F. Ruchatz, K. Kolter

Polymer dispersion

Kollicoat® MAE 30 DPTriethyl citratePropylene glycolWater

Polymer dispersion

Kollicoat® MAE 100 PTriethyl citratePropylene glycolWater

Pigment dispersion

Sicovit® Red 30Titanium dioxideTalcWater

Coating process (table 2)Test on stirring-in behaviorof Kollicoat® MAE 100 P anddetermination of viscosity9 kg Kollicoat® MAE 100 P (= 20%(w/w) dispersion) were stirred into36 kg water with immediate wet-ting of the powder. The stirrertorque and the viscosity were de-termined over a period of 3 h.

Determination of dissolutionAccording to USP 23, apparatus2, method B using 0.1 N HCl andphosphate buffer 6.8. Propranolol-HCl was determined spectrophoto-metrically at 289 nm.

ResultsStirring-in behavior,viscosity curveKollicoat® MAE 100 P is a flowablenon-dusting powder that can beincorporated rapidly and withoutproblems with stirring. Immediatewetting of the powder should beensured. During redispersion of thepowder, the viscosity increased to100 mPas in 5 minutes. This is be-cause the particles swell, produc-ing an intermediate viscous phaseon the surface, which causesfriction between the particles.The viscosity decreased to 30 mPasupon further stirring beyond 150

50.00

2.2532.25

61.80

3.7034.50

Spray formulations A B

18.00

2.2567.25

18.54 3.70

77.76

0.500.504.00

10.50

100.00 100.00

Coating parameters

Tablet mass 5 kgAtomizingnozzle 1.0 mm

Atomizingpressure 2.0 bar

Inlet airtemperature 50 °C

Outlet airtemperature 37 °C

Drying 5 min/50 °C



Viscosity-time curve(Figure 1)

Comparison ofdissolution rates ofKollicoat® MAE 30 DPand Kollicoat® MAE100 P coated tablets(Figure 2)

Coating level: 6 mg/cm2

Formulation A

Kollicoat® MAE 30 DPKollicoat® MAE 100 P

Dissolution rate as afunction of coating level(Figure 3)

Formulation B

Kollicoat® MAE 100 P,4 mg/cm2



Dissolution rate ofpropranolol HCl coreswith and withoutpigments(Figure 4)

Kollicoat® MAE 100 P,with pigmentsKollicoat® MAE 100 P,without pigments

minutes. No problems occurredwhen preparing the spray suspen-sions from the redispersible pow-der with or without pigments, orin the coating process.

Spraying processNo modification of process pa-rameters was necessary for appli-cation of the spray suspension ofKollicoat® MAE 30 DP and Kolli-coat® MAE 100 P. The sprayingbehavior was identical for bothproducts.

DissolutionAt a coating weight of 6 mg/cm2

polymer, propranolol-HCl-tabletsexhibited a dissolution rate of< 1 % after 2 h in 0.1 N HCl.In phosphate buffer pH 6.8 morethan 90% dissolved after 30 min-utes. The application of Kollicoat®

MAE 30 DP resulted in similardissolution characteristics. Visualinspections of all tablets after theacidic treatment showed that noswelling or other defects occurred.Even a reduced coating level of4 mg/cm2 (3.9 % after 2 h) easilyfulfilled the requirements of theUSP (< 10 % drug dissolution).The dissolution rate in buffer pH 6.8increases with decreasing coatinglevel. Even with a high coatinglevel of 12 mg/cm2 more than 80%was released after 30 minutes. Acoating of the same weight with-out pigments gave slightly higherdissolution rates in the acidic me-dium (2.4 % after 2 h).

Conclusions There was no differencein the gastric resistanceand drug dissolution rateof Kollicoat® MAE 30 DP(dispersion) and Kollicoat®

MAE 100 P (powder). In order to minimize theviscosity of a 20 % suspen-sion of Kollicoat® MAE 100 P,it should be stirred for atleast 3 h.

100

80

60

40

20

0

time [min]

visc

osi

ty [

mP

as]

0 60 120 3 6 9 12 15 30

100

80

60

40

20

0

time [min]

dis

solu

tio

n [

%]

0.1 N HCI Phosphate buffer pH 6.8

0 30 60 90 120 150

0 60 120 3 6 9 12 15 30

100

80

60

40

20

0

time [min]

dis

solu

tio

n [

%]


0 60 120 3 6 9 12 15 30

100

80

60

40

20

0

time [min]

dis

solu

tio

n [

%]




press. The compression force wasvaried between 5 and 25 kN. Thetabletting rate was 30 tablets/min-ute. The compression data wereevaluated using a BASF in-housesoftware program which calcu-lates the parameters listed intables 1 and 3.

Plasticity (%)plastic energy/total energy x 100.

Elastic relaxationtablet thickness without load –tablet thickness under load.

K-value (compression resistance)∆ log p / ∆ log qwhere p is the compression pres-sure, and q is the apparent density.

Results and DiscussionCompression of pure Kollidon® SRproduced tablets of exceptionalhardness. A compression forceof only 4.8 kN already gave a hard-ness value of 250 N, which in-creased to more than 500 N atcompression forces of 9.7 kN andabove. The values could not bemeasured since they exceeded thelimit of the measuring range of thehardness tester. These enormousstrengths were due to the plasticbehavior of polyvinyl acetate whichsoftens at increasing temperatures– occurring locally during thetabletting process – and becomeseasily deformable under pressure.This creates extremely strongbonds between the particles.The hollow conical structure ofKollidon® SR further enhances theplastic deformability and makes theparticles easy to compress.No overcompression effects wereobserved up to a compressionforce of 25 kN or 320 MPa, sincethe strength was always above

Kollidon® SRCompression behavior.K. Kolter

IntroductionSustained release matrix formu-lations are gaining increasingimportance because of their lowmanufacturing costs.Kollidon® SR is a relatively newmatrix retarding agent consistingof 80% polyvinyl acetate and 20%polyvinylpyrrolidone [1].

With its excellent flowability, thisformulated combination allowssustained release dosage formsto be manufactured by the simpledirect compression tabletting tech-nique. Although tablet formulationsare known to be easily produciblewith Kollidon® SR, no detailedstudies have yet been performedon the behaviour of Kollidon® SRduring tabletting.

ObjectiveThis study was undertaken tocharacterize the compression be-havior of pure Kollidon® SR, cor-relate the results with the tabletproperties and examine the influ-ence of admixed drug substance.

Experimental MethodsMaterialsKollidon® SR (polyvinyl acetate –polyvinylpyrrolidone, BASF Aktien-gesellschaft), caffeine 0.2–0.5(BASF Aktiengesellschaft).

MethodsAll starting materials were blendedfor 10 minutes in a Turbula mixerand compressed into flat tabletswith a diameter of 10 mm on aKorsch EKO instrumented tablet

4.8 kN 9.7 kN 14.4 kN 17.7 kN 25.0 kN

Hardness [N] 250 > 500 > 500 > 500 > 500Friability [%] 0 0 0 0 0Ejection force [kN] 0.10 0.04 0.03 0.02 0.02Residual force [kN] 0.05 0.00 0.00 0.00 0.00Energy of compression [J/g] 25.1 33.7 37.8 39.1 41.3Plasticity [%] 96.6 92.9 86.9 82.1 71.5Tablet thickness under load [mm] 4.41 3.78 3.57 3.48 3.31Relaxation in die [mm] 0.24 0.31 0.45 0.50 0.65

[%] 5.5 8.2 12.7 14.3 19.6Porosity under load [%] 36.8 19.0 15.0 13.2 9.4

without load [%] 41.1 25.1 24.6 24.1 24.2K-value 2.3 4.1 5.7 6.4 6.3Heckel constant [1/MPa] 0.0059 0.0076 0.0080 0.0128 -Heckel A-value 0.1664 0.1871 0.1925 0.1560 -

Table 3: Compression data of Kollidon® SR

Kollidon® SRCaffeineAerosil 200Magnesiumstrearate

Tablet weight

K-SR tablets

323.4 mg

1.6 mg

325.0 mg

K-SR/caffeine tablets

160.0 mg160.0 mg

3.5 mg

1.5 mg

325.0 mg

Table 1: Tablet formulations

9.9 kN 17.2 kN 25.0 kN

Hardness [N] 185 235 270Friability [%] 0 0 0Ejection force [kN] 0.17 0.13 0.12Residual force [kN] 0.09 0.06 0.04Energy of compression [J/g] 25.3 33.4 38.6Plasticity [%] 89.8 80.7 70.5Tablet thickness under load [mm] 3.82 3.50 3.32Relaxation in die [mm] 0.28 0.42 0.56

[%] 7.3 12.0 16.7Porosity under load [%] 33.3 28.1 24.9 without load [%] 37.9 35.8 35.7K-value 4.7 5.8 5.8Heckel constant [1/MPa] 0.0030 0.0023 0.0019Heckel A-value 0.2609 0.2955 0.3329

Table 2: Compression data of caffeine tablets (Kollidon® SR/caffeine 1:1)



Hardness of Kollidon®

SR and Kollidon® SR/caffeine tablets(Figure 1)

■ Kollidon® SR■ Kollidon® SR/

caffeine

Porosity of Kollidon® SRtablets as a function ofcompression force(Figure 2)

■ under load● without load

Plasticity of Kollidon® SRand Kollidon® SR/caffeine tablets(Figure 3)

● Kollidon® SR■ Kollidon® SR/

caffeine

Ejection force as afunction ofcompression force(Figure 4)

● Kollidon® SR■ Kollidon® SR/

caffeine

500 N and no friability was present.The admixture of caffeine, as ex-pected, reduced the strength tovalues between 185 and 270 N.The easy deformability of Kollidon®

SR is also manifested in the markeddecrease in porosity of the tabletsat low compression forces, andthe negligible change in porosityat moderate and high compres-sion forces. The porosity withoutload no longer changed fromabout 10 kN onwards, while theporosity under load still showed acertain decrease. In contrast, theK-value increased from a very lowinitial level.The plasticity of Kollidon® SRdecreases markedly with risingcompression force. This resultalso illustrates that Kollidon® SRis highly deformed even by slightpressure, but the elastic compo-nent increases considerably athigher pressures. This increase inthe elastic component of the en-ergy is associated with a greaterelastic relaxation of the tablet inthe matrix when the upper punchreturns upwards and the compres-sion force decreases (0.24 mm at4.8 kN and 0.65 mm at 25 kN).Surprisingly, these considerableelastic relaxations have no influ-ence at all on the strength of thetablet matrix.The addition of caffeine leads tolower plasticity values and lowerelastic relaxations in the die.Surprising results were also mea-sured for the ejection forces, sincethese values (0.10 to 0.02 kN) wereat an extremely low level yet stillcontinued decreasing as the com-pression force increased. The sameapplies for the residual force (0.05to 0.00 kN). From this it can be con-cluded that Kollidon® SR does notadhere to the die and that the re-laxation occurs rapidly and comple-tely in the direction of die opening.

References[1] Kollidon® SR TechnicalInformation; July 2001(BASF Aktiengesellschaft)

Conclusions Kollidon® SR yields tablets of exceptional strength even at lowcompression forces. The ejection forces and residual forces are very low and, surpris-ingly, continue decreasing as the compression pressure increases. Porosity, plasticity, elastic relaxation and K-value show thatKollidon® SR is an extremely easy to compress substance. Admixture of caffeine reduces the strength, elastic relaxationand plasticity, but increases the porosity and also – slightly –the ejection force. Kollidon® SR exhibits almost ideal tabletting properties.

500

400

300

200

100

0

250

> 500

235270

185

5 kN

ha

rdn

ess

[N

]

10 kN 18 kN 25 kN15 kN

> 500> 500> 500

0 5 10 15 20 25 30compression force [kN]

po

rosi

ty [

%]

50

40

30

20

10

0


pla

stic

ity

[%]

100

80

60

40

20

0


eje

cti

on

fo

rce

[k

N]

0.2

0.15

0.1

0.05

0



Solutol® HS 15 proved to havesuperior properties as a solubi-lizing agent because of its goodphysiological tolerance and highsolubilizing capacity for a widerange of drugs. Solutol® HS 15has been approved in parenteralformulations for human use inseveral markets.

ObjectiveThe purpose of the study was toshow some practical aspects of theproduction of micellar solutionswith Solutol® HS 15. Two differentformulation methods of solubiliza-tes were investigated with respectto the dissolution kinetics of vari-ous model drugs. The maximumamount of drug load using differ-ent batches of Solutol® HS 15was evaluated. The physiologicaltolerance of Solutol® HS 15 solu-bilizates was compared with poly-sorbate 80 (PS 80).

Solutol® HS 15Practical aspects for the production of solubilizates.K. Kolter, F. Ruchatz

IntroductionAn increasing number of drugs (es-pecially new entities) show a poorwater solubility causing seriousformulation problems for inject-ables. This has created a strongdemand for formulation aids toovercome the dissolution problems.

A simple and effective methodto dissolve drugs is their solubili-zation using non-ionic surfac-tants. Among these surfactants,

Materials and MethodsPreparation methodMethod A (RT): 20 % (w/w)Solutol® HS 15 was dissolved inphosphate buffer (PB) pH 7.0 (USPXXIII) at room temperature. An ex-cess of drug was added at thesame temperature under stirring.The dissolution kinetics of the dis-persion were monitored for 7 days.

Method B (65 °C): The drug wassuspended in the molten solubi-lizer (20% w/w) under stirring at65 °C. Phosphate buffer (PB) pH7.0 (USP XXIII) was added drop-wise and the solutions were al-lowed to cool to room tempera-ture under stirring.

DrugsClotrimazole, estradiole,sulfathiazole, nifedipine,riboflavin, carbamazepine,piroxicam, acetaminophenand tocopherol acetate wereused as model drugs.

Drug contentThe dispersions were filteredthrough a 0.22 µm membrane re-sulting in clear/opalescent solu-tions. After diluting the solubili-zates with a 1:1 mixture of metha-nol/PB, the amount of drug wasmeasured using a photometer(Hewlett Packard).

Laser light scatteringThe micelle diameters were mea-sured at an angle of 90°, by meansof a set up from ALV (Germany),equipped with a 400 mW Nd-Yag-Laser at 532 nm and a correlator(ALV 5000). The time correlationfunction was recorded for 15minutes and the hydrodynamicdiameter was evaluated using aCONTIN software program.

Haemolytic activity [% Haemolysis]

0.1% 1% 10%

0 1 51 4 58

Serum Histamine level [nMol]

0 min 15 min 60 min

5 220 83 > 50000 247

Table 3: Haemolytic activity of human erythrocytes and serum histamine level in dogs after i.v. application

HS 15PS 80

Method A Method B Method A Method B Method A Method B

Clotrimazole 0.27 0.28 270 280 3.45 3.52Estradiole 0.16 0.16 160 160 3.43 3.45Sulfathiazole 0.59 0.60 10 10 3.45 3.46Nifedipine 0.23 0.25 230 250 – –Carbamazepine 0.36 0.36 36 36 3.60 3.57Piroxicam 0.23 0.25 230 250 3.42 3.30Tocopherol acetate < 5 % 7.5 – – – 4.16

Drug amount [%] Diss. Enhance. Factor Kinematic Viscosity [mPas]

Table 2: Influence of the production method on the maximum amount of solubilizeddrug after 7 days and on the kinematic viscosity of the solubilizates

Method A Method B Method A Method B

Clotrimazole 12.7 13.0 206500 193400Estradiole 12.7 12.7 201600 184000Sulfathiazole 12.9 12.8 183400 179000Carbamazepine 13.0 12.9 185500 192600Piroxicam 12.7 12.7 168700 185400Tocopherol acetate 13.3 24.5 202000 1445700

Micelle diameter [nm] Mw [g/mol]

Table 1: Comparison of micells diameter and molecular weight [Mw]of solubilizates with different drugs and formulation methods



Conclusion The production of micellar drug solutions with Solutol® HS 15 is very easy. Economically,method B is preferred but for thermosensitive drugs an alternative way of production exists.Solutol® HS 15 shows a low toxicity combined with a high solubilizing capacity. Thus it can beregarded as an excellent solubilizer for parenteral use.

Kinematic viscosityThe solutions were investigatedat 25 °C using a capillary visco-simeter (Ubbelohde, Germany),capillary No. 1.

Haemolytic activityDifferent concentrations of thesolubilizers were incubated withisolated human erythrocytes for60 minutes. The degree of damageof the red blood cell membraneswas quantified by spectrophoto-metry of released haemoglobinafter centrifugation of the intacterythrocytes [1].

Blood histamine level in dogsSolubilizates of Solutol® HS 15 andPS 80 in a concentration of 5 % inan aqueous solution of 10% sorbi-tol were administered i.v. to beagledogs (100 mg/kg). The blood hista-mine level was monitored by sam-pling the blood in intervals over aperiod of 60 minutes. The amountof released histamine was ana-lyzed using an ELIZA test.

Results and DiscussionIn all cases, with the exception ofthe tocopherol acetate formulationproduced at room temperature,clear micellar solutions with a lowviscosity were obtained.

The comparison of the productionmethods revealed different disso-lution kinetics for the drugs(figure 1). Using method B, theelevated temperature of 65 °C ledto more or less supersaturatedmicellar drug solutions. However,the drug dissolution was finishedafter cooling to room temperaturewith the exception of piroxicamwithin 24 h, resulting in saturatedmicellar solutions. It can be ex-pected that the manufacture ofsolubilizates with drug amountsbelow the saturation point isfinished shortly after cooling toroom temperature. The maximumdrug load was reached in 6 of 8cases at 24 h when preparing thesolubilizates with method A.Generally after a period of 24 h,the drug concentrations in the mi-

cellar solutions were equal usingboth methods with the exceptionof tocopherol acetate. It seemsthat there is no influence of theproduction method on importantproperties of the solubilizates.As can be seen in table 2 at aconcentration of 20 % Solutol®

HS 15, the water solubility of thedifferent drugs could be enhancedby a factor of 10–100, dependingon the structure of the drug mole-cule. The micelle diameter and theviscosity were consistent, regard-less of the chemical structure ofthe drug or maximum amount ofsolubilized drug by using Solutol®

HS 15 (table 1, 2).

The kinematic viscosity of thesolubilizates was rather low. It canbe concluded that it is easily pos-sible to produce micellar solutionsof drugs using different methods.The diffusion and dissolution ofdrugs in a micellar solution at roomtemperature takes place veryquickly. For the handling of vita-mins like tocopherol acetate thedispersion in the molten solubilizeris needed, because mixed micel-les of vitamin/solubilizer are built.

As demonstrated in figure 2, dif-ferent batches of Solutol® HS 15showed the same solubilizationcapacity.

The results of the haemolytic studyand the measurements of the his-tamine release after i.v. applica-tion, indicated a low toxicity ofSolutol® HS 15 (table 3).

References[1] D. Hoover et al.,Fundam. Appl. Toxicol,14 (1990), 589 pp.

Dissolution kinetics of solubilizates of various model drugs withSolutol® HS 15 (Figure 1) ■ Method A (RT) ● Method B (65 ºC)

4

3

2

1

0

solu

bil

ize

d d

rug

[%

]

Estradiole Nifedipine AcetaminophenClotrimazole

■ 77–1763■ 67–1764■ 51–1772

Solubilization capacity of different batches of Solutol® HS 15

Nifedipine

0.400

0.300

0.200

0.100

dru

g c

on

ten

t [%

]

0 30 60 90 120 150 180time [h]

0.020

0.015

0.010

0.005

0.0000 30 60 90 120 150 180

time [h]

dru

g c

on

ten

t [%

]

Acetaminophen

6.000

5.000

4.000

3.000

2.0000 30 60 90 120 150 180

time [h]

dru

g c

on

ten

t [%

]

Piroxicam

0 30 60 90 120 150 180time [h]

0.500

0.400

0.300

0.200

dru

g c

on

ten

t [%

]

17-ß-Estradiole

0 30 60 90 120 150 180time [h]

0.300

0.200

0.100

0.000

dru

g c

on

ten

t [%

]

Carbamazepine

0.400

0.350

0.300

0.250

0.200

dru

g c

on

ten

t [%

]

0 30 60 90 120 150 180time [h]

Sulfathiazole0.800

0.600

0.400

0.2000

dru

g c

on

ten

t [%

]

30 60 90 120 150 180time [h]

Clotrimazole0.800

0.600

0.400

0.2000

dru

g c

on

ten

t [%

]

30 60 90 120 150 180time [h]

Riboflavin

Fig. 2



quirements, this plant will bealmost hermetically sealed fromthe filling station of raw materialsto the packing unit for finishedsubstances. In this way contami-nation of the products will beavoided and employees will haveabsolutely no contact with theactive ingredients. The plant hasbeen built according to an “easyto clean” design because of fre-quent product turnarounds.Twelve employees are currentlyworking in the multipurpose plantand the activities of the new plantwill create six further jobs.

multipurpose plant in Minden; twoare manufactured in the pilot plantsin Ludwigshafen. The two mainreasons for construction of thisplant are that the new plant willinclude state of the art technologyand that it will lead to a muchneeded increase in capacity forthe existing products. The FineChemicals Division intends to ex-pand its contract manufacturingactivities in order to produce moresubstances for the pharmaceuticalindustry. All products are manufac-tured under cGMP (current goodmanufacturing practice). In orderto meet stringent cleanliness re-

NewsA new multipurpose plant at Minden site.

BASF Fine Chemicals Divisionhas recently decided to investin a new plant in Minden.The new multipurpose plant en-tails the biggest investment evermade at Minden site. Building workstarted this summer and the plantwill be operational by the end of2004. Twelve active ingredientsand two intermediates will be pro-duced (toll-manufactured) for thepharmaceutical industry in thisnew plant. The Fine ChemicalsDivision has invested a doubledigit sum in this project.Twelve of the fourteen existingproducts are already produced in a



New MediaEdition 2003 now available.

Solutol® HS 15 monographed in the European Pharmacopoeia.

In recent years problems causedby solubilizers in pharmaceuticaldevelopment have become in-reasingly evident. In addition totoxicological problems, the solu-bilizing capacity of various solu-bilizers has also been the focusof research and development.

Solutol® HS 15, a solubilizer devel-oped by BASF, meets the require-

ments of an effective modern solu-bilizer and is approved for paren-teral applications. It has just beenmonographed in the EuropeanPharmacopoeia under the mono-graph name “Macrogol 15 hy-droxystearate”.

Beside the outstanding toxicologi-cal characteristics like a low hista-mine release compared to other

solubilizers also the good solubi-lizing capacity and the possibilityto sterilize solutions with Solutol®

HS 15 without stability problemsmake it an interesting material forthe pharmaceutical industry.

Technical InformationIn ExAct No. 10 we offered thefirst time the Technical Informa-tion “Products for the Food andPharmaceutical Industry”.

It covers the main technical dataon BASF vitamins, carotenoidsand other nutritional ingredientsfor the pharmaceutical and foodindustries.

Now the 2003 edition of thisTechnical Information is available.

This book/CD ROM can beordered with the attached replycard.



AsiaBASF Asia PacificRegional HQPharma SolutionsDr. Danilo MercadoBASF SouthEast Asia Pte Ltd35-01 Suntec Tower One7 Temasek Boulevard038987 SingaporePhone: +65/6398 5013Fax: +65/6430 [email protected]

EuropeBASF AktiengesellschaftMEE/HP-RheincenterMr. Peter HoffmannD-67056 LudwigshafenGermanyPhone: +49/621 60 7 69 28Fax: +49/621 60 7 69 [email protected]

NAFTABASF CorporationPharma SolutionsMr. Manuel Solbach3000 Continental Drive-NorthMount Olive, NJ 07828-1234USAPhone: +1/973 426 3877Fax: +1/973 426 [email protected]

South AmericaBASF S.A.Human Fine ChemicalsMs. Maria Celiade Paula RochaEstrada SamuelAizemberg, 170709851-550 São Bernardodo Campo – SPBrazilPhone: +55/11 43 43 33 11Fax: +55/11 43 43 22 [email protected]

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

Please contact your local BASF companyor one of the following regional centers:

Contact8th to 10th December, 2003

CPhI China 2003Shanghai, China

7th to 9th April, 2004Eighth European Symposiumon Controlled Drug DeliveryNoordwijk aan Zee, The Netherlands

21st to 23rd April, 2004CPhI Japan 2004Tokyo, Japan

29th May to 3rd June, 20042nd World Conference of the Boardof Pharmaceutical Sciences,Pharmaceutical Sciences World Congress(PSWC 2004)Kyoto, Japan

12th to 16th June, 200431st Annual Meeting & Exposition of theControlled Release Society,Honululu*, Hawaii, USA

4th to 9th September, 2004World Congress of Pharmacyand Pharmaceutical Sciences,64th Congress of FIPNew Orleans, USA

* BASF will be represented.

Calendar

ME

MP

030

775e

-00

Floating systems are particularlysuitable when a drug is intendedto exert its action locally in thestomach or is absorbed in thestomach or upper part of the smallintestine. These systems prolonggastric and intestinal transit time

and can thereby enhance bio-availability especially for drugswith an “absorption window”.To date only few manufacturingtechniques for floating systemsare known, all of them verydemanding.

PreviewSustained release floating systems based on Kollidon® SR.

ExAct No. 12 will include an articleon a simple, low-cost process forthe production of floating systemsby direct tabletting using Kollidon®

SR, a newly developed matrixsustained release excipient.

Scanned electronmicroscopy ofKollidon® SR

Content Dear Reader, · Dear Reader, pean Pharmacopoeia under the monograph name “Macrogol 15 hydroxystearate”. Beside the outstanding toxicologi-cal characteristics like a low

Documents