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Excipients & Actives for Pharma
No. 24, 2010
Today, in pediatrics, alarge number of drugsare unlicensed or pre-scribed off-label, i.e.despite a lack of in-formation on how toprescribe safely. Thus,the use of innovativemedication with chil-dren is often impos-sible. Moreover, in
general, off-label use is associated with more ad-verse reactions to drugs used for children. Not onlythat, the reactions may be more severe or differentfrom what is known from use in adults.
The EU regulations on the use of pediatric drugsrepresent a first step towards improved childhealth. BASF goes along with this approach byoffering Ludiflash, a directly compressible excipi-ent for orodispersibles. It can be applied suc-cessfully to the production of mini-tablets forpediatric use, enabling individual dosages to becalculated and making for easy administration toyoung patients. A further aid is our special safetyreport for Ludiflash which helps pharmaceuticalcompanies overcome regulatory hurdles in de-veloping medication for children.
Suitability of Plasticized Polymersfor Hot Melt Extrusion PAGES 2–6
Ludiflash®– Preparation and Charac-terization of Orally DisintegratingMini-Tablets for Pediatric Use PAGES 7–10
Ludiflash as Excipient forPediatric Use PAGE 11
Color Matching for Instant-Release Coated Tablets PAGES 12 – 14
Trouble-Shooting in Film Coating:Deposition and Sedimentation PAGES 15 – 16
PVP (polyvinylpyrrolidone):An All-Round Talent with Tradition PAGE 17
REGULATORY AFFAIRS PAGES 18 – 19
NEW MARKETING ASSETS PAGE 19
CALENDAR PAGE 20
PREVIEW PAGE 20
CONTACT PAGE 20
Innovative and promising technologies such ashot melt extrusion can be supported by the com-bination of various polymers with selected plas-ticizers and active ingredients. We provide furtherinsights in this edition: how are formulation prop-erties changed by certain additives, and what canbe used in order to achieve particular characteris-tics, either during processing or in the final formu-lation?
Find out how we can make drug developers moresuccessful in designing optimized and robust for-mulations, hence speeding up the developmentprocess. Our solubilization experts around theworld will be happy to discuss your solubilizationchallenges with you!
Yours sincerely,Dejan DjuricR&D Pharma Ingredients
Dear Reader: How can we overcome the hurdles involvedin medicating children?
Suitability of Plasticized Polymersfor Hot Melt Extrusion
CONTENTS
Designed to investigate the influence of several solubilizers and plasticizers on the extrusion processand extrudate characteristics, the present study shows, among other conclusions, that the combin-ation of certain materials can significantly change the glass transition temperature and the melt viscos-ity of the extrudate polymers. READ MORE ON PAGES 2 – 6
IN FOCUS
INTRODUCTION | Melt extrusion is a highlysuitable process for formulating sparingly solubledrugs and for improving bioavailability [1]. InExAct No. 22, we described the principle and thebasic requirements of the process [2]. The choiceof an appropriate polymer is crucial for the for-mulation and for the extrusion process. Polymersfor hot-melt extrusion (HME) should have thethermoplastic behavior to enable melt extrusionto take place and they have to be stable at theextrusion temperature. Other relevant character-istics are: a suitable glass transition temperature(Tg) of 50 to 180°C, low hygroscopicity and notoxicity, since large amounts of polymer are used[3]. The extrudability of a polymer is mainly de-termined by the Tg and the melt viscosity [4].Polymers of high molecular weight exhibit a highmelt viscosity and are difficult to extrude. More-over, a high Tg requires a high processing tem-perature, which can degrade sensitive actives [5].As a general rule, an extrusion process should berun at a temperature 20-40°C above the Tg. Poly-mer properties for hot-melt extrusion can be ad-justed by the use of plasticizers since thesematerials reduce the Tg and melt viscosity andalso facilitate the extrusion process [6, 7]. Lower-ing the extrusion temperature reduces degrada-tion and/or discoloration of the polymer andincreases drug stability in the pharmaceuticalformulation. Therefore, the study described herewas designed to investigate the influence of sev-eral plasticizers/solubilizers on the Tg, the meltviscosity, the temperature range for extrusion andthe extrudate characteristics of various polymers.
POLYMERS AND PLASTICIZERS | The poly-mers studied were: Kollidon® VA 64, Kollidon 12PF, Kollidon 17 PF, Kollidon 30, Kollidon 90 F,Kollidon SR, Soluplus®, Kollicoat® MAE 100P,Kollicoat IR and Lutrol® F 127 (BASF SE, Ger-many). The plasticizers studied were: Lutrol F 68,Cremophor® RH 40 and Pluriol® E 1500 Powder K(PEG 1500) (BASF SE, Germany).
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Page 2
PUBLISHER:
BASF SEPharma Ingredients & Serviceswww.pharma-ingredients.basf.com
EDITORIAL STAFF:
Alexandra BrandAndres-Christian OrthoferKarl KolterVanessa Occhipinti
AUTHORS:
Angelika MaschkeClaudia EasterbrookDorothee-Christine KrihaChristian BeckerFlorian WildschekFriederike OsswaldInes StoltenbergJörg BreitkreutzKarl KolterMatthias KarlMichael Gerrit HertingPhilipp HebestreitRalf WidmaierSebastian HoeferThorsten CechThorsten Schmeller
CONCEPT/LAYOUT:
Château Louis Strategische Markenführungund Kommunikation GmbH
PRINT:
johnen-druck GmbH & Co. KG
IMPRINT RESULTS AND DISCUSSION | All polymerswere characterized by their glass transition tem-perature (Tg), melt viscosity and degradationtemperature (T(degradation)) as indicated by onsetof mass loss in thermogravimetric measurements(TGA).
Taking these characteristics into consideration,Soluplus, Kollidon VA 64 and Kollidon 12 PFdemonstrated excellent suitability for extrusion.Kollidon 17 PF, Kollidon SR and Kollicoat IR weredifficult to extrude because of the higher Tg orTm (melting point), melt viscosities and thesmaller difference of T(degradation) to Tg or Tm(Figure 1). Povidones of higher molecular weight(Kollidon 30 and Kollidon 90 F) and Kollicoat MAE100P exhibited poorer values in this respect andwere not processable by HME as pure polymers.A large range between Tg and T(degradation) ishighly beneficial because it offers more freedomfor the development of the extrusion process andalso serves as a prerequisite for a reliable andreproducible formulation.
Trademarks are owned by BASF SE
IN FOCUS
No. 24, 2010Excipients & Actives for Pharma
Suitability of Plasticized Polymersfor Hot Melt ExtrusionM. Karl, K. Kolter
A large range betweenthe glass transition tem-perature and degradationtemperature of the poly-mers is highly beneficialbecause it offers morefreedom for the develop-ment of the extrusionprocess.
Subsequently, the influence of plasticizers suchas Lutrol F 68, Cremophor RH 40 and PEG 1500on the above-mentioned parameters was inves-tigated (Figures 2 and 3). In systems comprisingPEG 1500 and Cremophor RH 40, the resultsshowed a pronounced tendency to decrease theTg of the polymers. In polymer combinations withLutrol F 68, the Tg of the vinylpyrrolidone poly-mers was practically unaffected by this com-pound [8].
The impact of plasticizers on the melt viscosity ofKollidon VA 64 is illustrated in Figure 4. A consid-erable reduction of the melt viscosity wasachieved by adding plasticizer, increasing in thefollowing order: Cremophor RH 40 < PEG 1500 <Lutrol F 68. Since Lutrol F 68 reduced the meltviscosity substantially but did not significantly af-fect Tg, it can be concluded that it is probably notcompletely miscible with the polymers tested.
The plasticizer-polymer combinations character-ized by lowered Tg and melt viscosity extendedthe temperature range for extrusion since thiscould be performed at lower temperatures [9].Melt extrusion studies to determine the lower endof the temperature range revealed the strongesteffect for PEG 1500 (Figure 5). This can be attrib-uted to the strong decline of Tg as well as to thesignificant reduction of melt viscosity.
Page 3
FIGURE 1 Comparison of the Tg or Tm (by DSC) with the temperature of degradation (by TGA) of pure polymers
FIGURE 2 Tg of pure polymers in comparison with polymer-plasticizer combinations (extrudates, 9:1, w/w-%)
No. 24, 2010Excipients & Actives for Pharma
180
160
140
120
100
80
60
40
20
0
KollidonVA 64
Soluplus
Tg[°
C]
101103
83
54
Kollidon 12PF
Kollidon 17PF
70
47 5042
90 92
7167
138137
109102
300
Tem
pera
ture
[°C]
250
200
150
100
50
Kolli
don
VA64
Kolli
don
12PF
Kolli
don
17PF
Kolli
don
30
Kolli
don
90F
Kolli
don
SR
Solu
plus
Kolli
coat
MAE
100P
Kolli
coat
IR*
Lutro
lF12
7*
0
Tg (or *Tm)
T degradation
101
230
90
225
138
175
149
175156
200
152
210
70
250
114
150
208 200
55
180
Pure polymer
Lutrol F 68
Cremophor RH 40
PEG 1500
Page 4
FIGURE 3 Tg of pure polymers in comparison with polymer-plasticizer combinations (extrudate and film (*), 9:1, w/w-%)Split bars represent the presence of another Tg
No. 24, 2010
FIGURE 4 Melt viscosity of Kollidon VA 64 in comparison with Kollidon VA 64 / plasticizer combinations (9:1, w/w-%)
The extrudates of Kollidon® VA 64 obtained usingPEG 1500 as the plasticizer were transparent,whereas extrudates with Lutrol® F 68 and Cre-mophor® RH 40 were opaque. For both opaquesystems, the signals produced by Lutrol F 68 andCremophor RH 40 respectively were monitored bydifferential scanning calorimetry (DSC). For thetransparent extrudate with PEG 1500, no PEG1500 signal was observed. In accordance withthese findings, in combination with Lutrol F 68, theTg of Kollidon VA 64 at approx. 101°C could stillbe determined and in the cases of CremophorRH 40 and PEG 1500, the Tg was shifted to lowertemperatures [10].
Based on these DSC results (Figures 6 to 8) andon visual inspection, it can be concluded that PEG1500, in contrast to the others, forms a single-phase mixture when melt-extruded with KollidonVA 64. In other words, it is completely miscible.
2532
18
39
152 155
118
156
146
133128
149
129
101
118
180
160
140
120
100
80
60
40
20
0
Kollidon 30 (*) Kollidon 90 F (*) Kollidon SR
Tg[°
C]
10
Temperature [°C]
Visc
osity
[Pa*
s]
100
1000
10000
140 150 160 170 180 190 200 210
Optimummeltviscosityrange forHME
Excipients & Actives for Pharma
Pure polymer
Lutrol F 68
Cremophor RH 40
PEG 1500
Kollidon VA 64
Kollidon VA 64 / Cremophor RH 40 (9:1)
Kollidon VA 64 / Lutrol F 68 (9:1)
Kollidon VA 64 / PEG 1500 (9:1)
Page 5
FIGURE 5 Temperature range for extrusion of the pure polymers in comparison with polymer / PEG 1500 combination (9:1, w/w-%)
No. 24, 2010
FIGURE 6 DSC plot of Kollidon VA 64, Lutrol F 68 and a combination of Kollidon VA 64 / Lutrol F 68 (extrudate, 9:1, w/w-%)
REFERENCES
[1] C. Leuner and J. Dressman, Improving drugsolubility for oral delivery using solid disper-sions, European Journal of Pharmaceuticsand Biopharmaceutics, 50, 47-60 (2000)
[2] K. Kolter and A. Maschke, Melt Extrusion forPharmaceuticals, ExAct, No. 22 (2-5) (2009)
[3] I. Ghebre-Sellassie, C. Martin, Pharmaceuti-cal Extrusion Technology, Drugs and thePharmaceutical Sciences, Volume 133 (2007)
[4] R. J. Chokshi, H. K. Sandhu, R. M. Iyer, N.H.Shaw, A. W. Malick and H. Zia, Character-ization of physico-mechanical properties ofindomethacin and polymers to assess theirsuitability for hot melt extrusion processesas a means to manufacture solid disper-sion/solution, Journal of PharmaceuticalScience, 94, (11, 2463-2474 (2005)
[5] S. Thumma, M. A. ElSohly, S. Q. Zhang,
Temperature [°C]
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240
Heat
flow
[W/g
]
8
6
4
2
0
-2-100 -50 0 50 100 150 200
Temperature [°C]
Extrudate:Kollidon VA 64 / Lutrol F 68
Kollidon VA 64
Lutrol F 68
Kollidon VA 64 / Lutrol F 68
Kollidon VA 64
Kollidon 12 PF
Kollidon 17 PF
Kollidon SR
Soluplus®
Kollicoat® IR
Pure polymer
+ 10% PEG 1500
CONCLUSION
� The type of plasticizer used has a major im-pact on the relevant characteristics of theextrusion process and the extrudates. Plas-ticizers influence the Tg, melt viscosity, tem-perature range for extrusion and extrudateproperties.
� The addition of PEG 1500 and CremophorRH 40 reduces the Tg of the polymer con-siderably.
� All plasticizers lowered the melt viscositywhen added to Kollidon VA 64.
� All plasticizers extended the lower end ofthe temperature range for extrusion, but thiswas most pronounced with PEG 1500.
� The presence of plasticizer signals in DSCruns correlates with the appearance of extru-dates and indicates miscibility or non-misci-bility on a molecular basis. |
Excipients & Actives for Pharma
Page 6
No. 24, 2010
W. Gul, M. A. Repka, European Journal ofPharmaceutics and Biopharmaceutics, 70(2), 605-614 (Oct. 2005)
[6] A. Ghebremeskel, C. Vemavarapu andM. Lodaya, Use of surfactants as plasti-cizers in preparing solid dispersions ofpoorly soluble API, International Journal ofPharmaceutics, 328, 119-129 (2007)
[7] M. A. Repka, S. Majumdar, S. K. Battu, R.Srirangam and S. B. Upadhye, Applicationsof hot-melt extrusion for drug delivery, Ex-pert Opinion on Drug Delivery, 5 (12):1357-1376 (2008)
[8] M. Baiardo, G. Frisoni, M. Scandola,M. Rimelen, D. Lips, K. Ruffieux, E. Winter-mantel, Thermal and mechanical propertiesof plasticized poly (L-lactic acid), Journal ofApplied Polymer Science, 90 (7), 1731-1738(Sep. 2003)
[9] C. B. Wu, J. W. McGinity, Influence ofmethylparaben as a solid-state plasticizer onthe physicochemical properties of Eudragit®
RS PO hot-melt extrudates, European Jour-nal of Pharmaceutics and Biopharmaceutics,56 (1), 95-100 (Jul. 2003)
[10] K. Okamoto (Okamoto, Kenzo); T. Ichikawa(Ichikawa, Tomokazu); T. Yokohara (Yoko-hara, Tadashi); M. Yamaguchi (Yamaguchi,Masayuki); Miscibility, mechanical and ther-mal properties of poly (lactic acid) / poly-ester-diol blends, European Polymer Journal,45 (8), 2304-2312 (Aug. 2009)
Heat
flow
[W/g
]
3
2
1
0
-1-100 -50 0 50 100 150 200
Temperature [°C]
Extrudate:Kollidon VA 64 / Cremophor RH 40
Kollidon® VA 64
Cremophor® RH 40
Kollidon VA 64 /
Cremophor RH 40
Heat
flow
[W/g
]
10
8
-100 -50 0 50 100 150 200
Temperature [°C]
Extrudate:Kollidon VA 64 / PEG 1500
Kollidon VA 64
PEG 1500
Kollidon VA 64 / PEG 1500
6
4
2
0
-2
FIGURE 7 DSC plot of Kollidon VA 64, Cremophor RH 40 and a combination of Kollidon VA 64 / Cremophor RH 40(extrudate, 9:1, w/w-%)
FIGURE 8 DSC plot of Kollidon VA 64, PEG 1500 and a combination of Kollidon VA 64 / PEG 1500 (extrudate, 9:1, w/w-%)
Excipients & Actives for Pharma
Page 7
No. 24, 2010
CHILDREN´S MEDICATION
Ludiflash®– Preparation and Characterization of OrallyDisintegrating Mini-Tablets for Pediatric UseI. Stoltenberg, J. Breitkreutz (Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Düsseldorf, Germany)
INTRODUCTION | Young children often haveno access to suitable medicines. To deal withthis, both the US and the EU authorities imple-mented new pediatric regulations requiringincreased efforts in the development of pediatricformulations. The desired properties of pediatricdosage forms are easy administration, good oracceptable taste, the possibility for dose titrationand safe excipients.Orally-disintegrating mini-tablets (ODMTs) aredefined as small tablets with a diameter of 3 mmor less and a disintegration time of less than 30seconds. These are particularly suitable foryounger children (> 1 month) [1]. Easy adminis-tration without the need for additional water is amajor advantage. Due to the fast disintegrationof the tablets, it is difficult for children to spit themout. Furthermore, they may provide accurate indi-vidualized dosing, for example according to thebody weight or body surface area of the children.
In addition, two or more mini-tablet formulationscan be combined to generate fixed dose combin-ations of different active pharmaceutical ingredi-ents (APIs). The combination of mini-tabletsbased on various release principles is a furtherpossibility. ODMTs provide the convenience of atablet formulation but also the ease of swallowingallowed by liquid formulation.They can be manufactured using conventionaltableting facilities but necessitate excipientswhich fulfill the requirements for direct compres-sion of tablets. The excipients should have goodflow characteristics and good compactibility,especially with regard to the small-dimensionedmini-tableting tool. Ludiflash is a new coprocessedready-to-use excipient for fast-disintegrating oraldosage forms. It is made from D-mannitol, cros-povidone (Kollidon CL-SF, BASF SE), polyvinylacetate (Kollicoat® SR 30D, BASF SE) and povi-done (Kollidon 30, BASF SE). All componentscomply with leading pharmacopoeia mono-graphs. Concerning the high amount of sweet-tasting but non-cariogenic D-mannitol (90%),
> orally-disintegrating tablets made with Ludiflashshould prove to be very palatable for children.D-mannitol is deemed to be a safe excipient forchildren [2].
PURPOSE | The purpose of this study was toinvestigate the feasibility of Ludiflash as an ex-cipient for the direct compression of ODMTs forpediatric use.
METHODS AND MATERIALS | MaterialsLudiflash (BASF SE), sodium stearyl fumarate(Pruv®, JRS Pharma), magnesium stearate (Bär-locher GmbH).
Experimental design An eleven-run full fac-torial design (including three replicates of thecenter point) was used to evaluate three variables(type of lubricant, lubricant concentration andcompression force) with respect to the ODMTsproperties, crushing strength and simulated wet-ting test time.
Preparation of mini-tablets All ingredientswere blended in a Turbula blender (Bachofen SE)for 10 minutes and directly compressed intobiconvex mini-tablets of 2 mm diameter using arotary tablet press (Pressima MX-EU-B/D, IMAKilian GmbH & Co KG) with one 19-tip mini-tableting tool (Ritter Pharmatechnik GmbH).
Simulated Wetting Test (SWT) The wettingtime of the ODMTs was evaluated according to amethod described by Park et al [3]. One What-man filter paper disk (5 mm in diameter) wasplaced in each well of a 96-well plate. 20 µl of0.1% (w/w) Brilliant Blue 85 E 133 solution (BASFSE) was added to each well. One ODMT wascarefully placed on the surface of the wet paperdisk in each well using a pair of forceps. The levelof the dye solution did not cover the tablet. Thetime required for the blue dye solution to wet thetablet completely was measured as the simulatedwetting test time.
Crushing strength The crushing strength wasmeasured using a texture analyzer (TA-XT2i,Stable Micro Systems). [4]
Flowability The flowing properties of the pow-der blends were determined using a ring sheartester RST-01.pc (Dr. Dietmar Schulze, Schuett-gutmesstechnik). The ratio ffc of consolidationstress σ1 to unconfined yield strength σc wasused to characterize flowability numerically (Table1). The pre-shear normal stress was constant atabout 5000 Pa.
The desired properties ofpediatric dosage formsare easy administration,good or acceptable taste,the possibility for dosetitration and safe excipi-ents.
TABLE 1 Flow behavior according to theclassification used by Jenike [5]
ffc <1
1<ffc<2
2<ffc<4
4<ffc<10
Not flowing
Very cohesive
Cohesive
Easy-flowing
10<ffc Free-flowing
Numerical characterization of flowability
Excipients & Actives for Pharma
RESULTS AND DISCUSSION | Preliminaryexperiments The flowability of blends of Ludi-flash® and used lubricant were tested using thering shear cell. All samples showed an ffc value>10, which implies excellent flow properties. Thisallows uniform filling of the small dies during thetableting operation. Since mini-tableting tools arevery fragile, good compactibility properties arerequired. Preliminary experiments indicated thatonly low forces (<10 kN for the 19-tip tool) wereneeded to obtain regularly shaped Ludiflash mini-tablets (Figure 1) with a sufficient crushingstrength (between 4 and 11 N) (Figure 3).
Results of the experimental design (Table 2)All mixtures of the statistical experimental setupcould be compressed into mini-tablets. ODMTswith sodium stearyl fumarate as the lubricant hada significantly lower wetting time in the SWT thanODMTs with the more hydrophobic magnesiumstearate (Figures 2, 4). Increasing lubricant con-centration had a negative impact on the SWTtime in all cases; however, the influence on theODMTs with sodium stearyl fumarate proved tobe of minor importance. Higher compressionforces resulted in longer SWT times, independ-ent of the type of lubricant (Figure 4).
The considerable influence of the compressionforce on the crushing strength is shown in Figure5. In contrast to sodium stearyl fumarate, mag-nesium stearate decreased the crushing strengthof ODMTs. The concentration of lubricant had nosignificant effect. In our experiments, Ludiflashshowed excellent properties for producingODMTs.
Page 8
TABLE 2 Results of the experimental design
No. 24, 2010
FIGURE 2 Simulated wetting test of an ODMTs with 5%magnesium stearate, produced with 3 kN
FIGURE 1 ODMTs made from Ludiflash and 3%sodium stearyl fumarate (2 mm diameter)
N1
Type of lubricant Lubricantconcentration
[%]
Compressionforce
[kN]
SWT time
(n=10)[s]
Crushingstrength
(n=30)[N]
Sodium stearyl fumarate
N2
N3
N4
N5
N6
N7
N8
N9
N10
N11
Magnesium stearate
Sodium stearyl fumarate
Sodium stearyl fumarate
Sodium stearyl fumarate
Sodium stearyl fumarate
Sodium stearyl fumarate
Sodium stearyl fumarate
Magnesium stearate
Magnesium stearate
Magnesium stearate
2
2
2
2
5
5
5
5
3.5
3.5
3.5
3
3
3
3
8
8
8
8
5.5
5.5
5.5
1.55
3.25
2.17
7.78
3.42
6.68
6.17
21.05
2.96
2.94
2.89
4.80
4.11
4.49
3.95
10.78
10.76
11.99
9.31
8.31
8.80
8.04
0 s 4 s 6 s
8 s 10 s
Excipients & Actives for Pharma
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No. 24, 2010
FIGURE 3 Crushing strength and compression force profile of Ludiflash-ODMTs with 3% sodium stearyl fumarate,n=30, mean ± SD, R²=0.9982
CONCLUSION | Orally disintegrating mini-tabletsare supposed to be very useful formulations forthe treatment of young children and may be con-sidered as a new technology platform in pedi-atrics. The criteria of theWorld Health Organization(WHO), such as the use of standard excipientsand conventional techniques, are fully met [6].Due to its excellent properties for the direct com-pression of mini-tablets (good flowing behavior,good compactibility), Ludiflash is suitable formanufacturing this new dosage form. The lubri-cant sodium stearyl fumarate outperforms mag-nesium stearate in crushing strength and SWTtime. A compression force between 5 and 8 kN(approx. 80-130 MPa) should be applied toachieve ODMTs with sufficient crushing strength(above 8 N). Excellent SWT times of less than 4seconds were obtained using 2-3.5% sodiumstearyl fumarate. |
Compression force [kN]
Crus
hing
stre
ngth
[N]
14
12
10
8
6
4
2
0
0 2 4 6 8 10
FIGURE 4 Coefficient plot for the simulated wetting test time; R²adj. = 1.000, Q² = 0.999; sodium stearyl fumarate (Sostefu),magnesium stearate (Mgste), lubricant concentration (LC), compression force (CF)
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
-0.10
-0.15
-0.20
-0.25
Soste
fuMgs
te LC CF
Soste
fu*LC
Mgste*
LC
Soste
fu*CF
Mgste*
CFLC
*SF
Sim
ulat
edw
ettin
gte
sttim
e[s
]
Excipients & Actives for Pharma
Page 10
No. 24, 2010
FIGURE 5 Coefficient plot for the crushing strength; R²adj. = 0.932, Q² = 0.603, sodium stearyl fumarate (Sostefu), magnesiumstearate (Mgste), lubricant concentration (LC), compression force (CF)
REFERENCES
[1] Krause J, Breitkreutz J. Improving drug deliv-ery in pediatric medicine. Pharm Med. 2008;22:41-50
[2] Breitkreutz J. Kindgerechte Arzneizube-reitungen zur peroralen Anwendung, Habili-tationsschrift, 2004
[3] Park J. H., Holman K. M., Bish G. A., KriegerD.G., Ramlose D. S., Herman C. J., Wu S. H..An alternative to the USP disintegration testfor orally disintegrating tablets. Pharm. Tech.2008; 32:54-58
[4] Mittwollen J-P. Verdichtungsverhalten, Fes-tigkeit und Struktur von planen Minitabletten,Dissertation, 2002
[5] Jenike AW. Storage and flow of solids. Bull.No. 123; Engng. Exp. Station, Univ. Utah,Salt Lake City; 1964
[6] WHO, Report of the informal expert meetingon dosage forms of medicines for children.http://www.who.int/selection_medicines/-committees/expert/17/application/pae-diatric/Dosage_form_reportDEC2008.pdf.Accessed December 15, 2009
Soste
fuMgs
te LC CF
Soste
fu*LC
Mgste*
LC
Soste
fu*CF
Mgste*
CFLC
*SF
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
-0.10
Crus
hing
stre
ngth
[N]
Excipients & Actives for Pharma
Page 11
No. 24, 2010
Ludiflash® is a formulation for fast-disintegrat-ing solid oral dosage forms. The formulation ofco-processed ingredients consists of three com-pendial excipients: D-mannitol, crospovidone(Kollidon® CL-SF) and a polymer dispersionbased on polyvinyl acetate (Kollicoat® SR 30 D).It is designed to disintegrate on the tongue withina few seconds, giving a pleasant mouthfeel. Ludi-flash is suitable for direct compression manufac-turing by simply blending the excipient with theactive ingredient and a lubricant; it is thus a verycost-efficient production method.
Many drugs are currently not available in formu-lations suitable for administration to pediatric pa-tients.
Ludiflash, formulated as orally disintegrating mini-tablets (ODMTs), is especially suitable for pediatricuse and may be considered an innovative tech-nology platform for pediatric formulations.With Ludiflash, such ODMTs can be obtained insizes as low as 1 mm diameter. Disintegration ofsuch small ODMTs can be complete within a sec-ond or less than 10 seconds, depending on sizeand formulation.
>
Considering the recent development and currentregulations on pediatrics (Regulation (EC) No1901/2006 of the European Parliament and of theCouncil of 12 December 2006 on medicinal prod-ucts for pediatric use and amending Regulation(EEC) No 1768/92, Directive 2001/20/EC, Direct-ive 2001/83/EC and Regulation (EC) No 726/2004and/or concept paper on the development of aquality guideline on pharmaceutical develop-ment and medicines for pediatric use,EMEA/138931/2008), BASF decided to supportits customers by creating a special safety reportfor Ludiflash.
Ludiflash comprises 84.0-92.0% mannitol, 4.0-6.0% crospovidone, 3.5-6.0% polyvinyl acetateand 0.25-0.60% povidone (component of Kolli-coat SR 30 D). A summary of the relevant safetydata in the scientific literature and BASF’s own
safety data have been compiled. This safety datasheet is available upon request and also on thecompany’s webpage http://www.pharma-ingre-dients.basf.com/ludiflash/default.aspx. Extensivesafety and toxicological reports performed byBASF are available under a secrecy agreement.In summary, the safety report reveals that there areno hindrances stemming from toxicological stud-ies or clinical experiences with Ludiflash to pre-vent use of the excipient in pediatric patients.
REFERENCES
[1] J. Breitkreutz, J. Boos, Exp. Opin. Drug Deliv.4: 37-45 (2007)
|
CHILDREN´S MEDICATION
Ludiflash® as Excipient for Pediatric UseP. Hebestreit, F. Osswald, R. Widmaier, M. G. Herting
Considering the recentdevelopment and currentregulations on pediat-rics, BASF decided tosupport its customers bycreating a special safetyreport for Ludiflash.
1. Sufficient bioavailability (despite children´s particularities)
2.
3.
4.
5.
6.
7.
8.
Non-toxic excipients regarding age group and administration
Palatable or acceptable organoleptic properties
Acceptable dose uniformity
Easy and safe administration
Socio-cultural acceptability (no stigmatization)
Precise and clear product information
Convenient for parents
Criteria for drug dosage forms appropriate for children [1]
Excipients & Actives for Pharma
The experimental setup for colorimetric evalua-tion was: aperture USAV, light source d65 andobserver angle 10°. The colorimetric values wererecorded as L*a*b* values of the CIELAB colorspace and color deviation was calculated by de-termining the Delta E value as displayed in Equa-tion 1.
Page 12
No. 24, 2010
INTRODUCTION | Color plays an importantrole in the development of solid oral dosageforms. Regarding the safety of tablets, fast iden-tification, not only by shape and size, but color, isof great advantage. Although patients prefersmall white tablets, colored tablets increase bothdrug safety and patient compliance [1]. Often,tablets containing the same drug but varying instrength are of a different color to help patientsdistinguish between them. This is particularly thecase for elderly patients undergoing multi-drugtreatment as the differentiation of tablets by coloris enhanced. Furthermore, the psychologicaleffect of color can increase drug efficacy [2].From a marketing point of view, the recognitionvalue of a color can be used to create a specialbrand. The new product range of Kollicoat® IRCoating Systems – consisting of 7 ICH-approvedbasic colors – for example has been designed tofacilitate the convenient and short production ofinstant release coated tablets of a certain color[3]. This is done by combining the different basiccolors at the production plant. The coating sys-tems are composed of the film-forming polymerKollicoat IR, a PEG-PVA grafted copolymer [4],pigments and further additives. Special softwarehas been developed that makes the color predic-tion of combinations of the different basic colorspossible. The goal of this study was to investi-gate the potential to produce tablets of a certaincolor using the Kollicoat IR Coating Systems incombination with a color matching functionbased on an algorithm of the colorimetric data ofthe colors. Evaluation was performed by colormatching products already on the market.
MATERIALS | Instant release colored coatingsystems Kollicoat IR White II, Kollicoat IR Yellow,Kollicoat IR Red, Kollicoat IR Carmine, KollicoatIR Sunset Yellow and Kollicoat IR Brilliant Blue(BASF SE, Germany) were used as coatingmaterials. The coloring pigments were titaniumdioxide, iron oxide yellow/red, and the aluminum
>
Color Matching for Instant Release Coated TabletsA. Maschke, T. Schmeller, K. Kolter
lakes Carmine, Sunset Yellow and Brilliant Blue,respectively. The core formulation of the tabletswas 99.5% Ludipress® LCE (BASF SE, Germany)and 0.5% magnesium stearate (BaerlocherGmbH, Germany).
METHODS | The first step in the color matchingprocedure was to determine the color of the ori-ginal tablets by colorimetric evaluation (Datacolor400, Datacolor, USA). Based on the L*a*b* valuesobtained, recipes for color matching were calcu-lated using the previously-mentioned algorithm.The color of the tablets coated with the sug-gested formulations was determined and thecolor deviation then evaluated. Color adjustmentwas carried out by adapting the recipes (seeFigure 1).
FILM COATING
EQUATION 1 Equation to calculate Delta E value
FIGURE 1 Schematic color matching procedure
Color or tablet selection
Color measurement
Recipe calculation with algorithm
Film coating of tablets
Color measurement of tablets
Determination of color deviation Delta E
Color adjustment
∆ E = (L*1- L*2)2 + (a*1- a*2)2 + (b*1- b*2)2 (1)
Excipients & Actives for Pharma
Page 13
No. 24, 2010
FILM COATING | Tablets were coated using afluid bed coater with a central rotating sprayingnozzle (Ventilus IEV1, Innojet Herbert Huettlin),Germany). Aqueous film coating suspensionswith 20% solids content were prepared by redis-persion of mixtures of the Kollicoat IR CoatingSystems in water. For the film coating trials, abatch size of 150 g was used and the coatinglevel was set to 3.2% weight gain (4.9 mg/cm2).
RESULTS AND DISCUSSION | By simply com-bining the different colored Kollicoat IR CoatingSystems, a large color space became accessible,as shown for 100 colors in Figure 2.For testing color matching, 10 commerciallyavailable tablets of different color shades wereselected. The colorimetric data were used (seeTable 1) to calculate the recipes for color match-ing (see Table 2). Those recipes with the smallestvariation of basic colors were selected. In evalu-ating the L*a*b* values of the matched tablets,color deviations below a Delta E of 2.5 were ob-served (see Figure 3). This color deviation is usu-ally not detectable by the untrained eye, whenapplied to the relatively small dimensions of atablet. Furthermore, even within one batch ofcoated tablets, color differences of up to a DeltaE of 3 were detected (data not shown).
The color matching procedure is an iterativeprocess; therefore, generating a matching recipewithin the first cycle is an excellent result. To showthe effect of adjusting the recipe, a color match-ing process in two steps is shown in Table 3.Evaluation of the L*a*b* values showed that low-ering the red and yellow pigment content reducedthe Delta E. Exchanging Kollicoat IR Red by Kolli-coat IR Sunset Yellow in the recipe further reducedthe Delta E from 2.0 to 1.3.
FIGURE 2 2D visualization of L*a*b* values of 100 different tablet colors coated with mixtures of Kollicoat IR Coating Systems
TABLE 1 Colorimetric data of marketed products
Tablet Color L* a* b*
1
2
3
4
5
6
7
8
9
10
yellow
yellow
yellow
orange
pink
red
red
green
blue
blue
81.0
74.7
72.6
92.4
88.7
88.6
74.9
14.1
12.4
24.9
27.0
8.4
65.6
75.4
69.4
3.5
11.4
-7.7
-8.1
-7.3
28.5
40.7
21.4
19.9
10.8
23.3
8.9
7.1
-18.7
-21.7
60
50
40
30
20
10
0
-10
-20
-30
-40
-40 -30 -20 -10 0 10 20 30 40 50 60
-a*
-b*
+b*
+a*
100
80
60
40
20
0
L*
Excipients & Actives for Pharma
CONCLUSION | The Kollicoat IR Coating Sys-tems product line enables the color matching oftablets. In combination with a BASF-proprietaryalgorithm, a fast and economical color matchingprocedure is possible. Due to the large accessiblecolor space, a desired color can be prepared bythe combination of different Kollicoat IR CoatingSystems.
REFERENCES
[1] AJM deCraen, PJ. Roos, AL. deVries AL,J. Kleijnen, Effect of color of drugs, BMJ,313, pp 1624-1626 (1996)
[2] A.B.A. Overgaard, J. Møller Sonnergaard,L.L. Christrup, J. Højsted, R. Hansen, Pa-tients' evaluation of shape, size and colourof solid dosage forms, Pharmacy World &Science Volume (23) 5, pp 185-188 (2001)
[3] A. Maschke, T. Schmeller, K. Kolter, Influenceof coating parameters on instant releasecoated colored tablets, AAPS 2009
[4] V. Bühler, Kollicoat Grades Functional Poly-mers for the pharmaceutical industry (2007)
|
Page 14
No. 24, 2010
TABLE 2 Recipes for color matching
FIGURE 3 Delta E values of color-matched tablets
The color matching proced-ure is an iterative process;therefore, generating amatching recipe within thefirst cycle is an excellentresult.
TABLE 3 Refinement of color matching
Tablet White ||
[%]
Yellow
[%]
Red
[%]
SunsetYellow
[%]
1
2
3
4
5
6
7
8
9
10
85.0
50.0
95.7
87.2
97.3
75.0
98.5
88.3
98.4
92.5
14.0
49.6
4.6
4.3
1.7
11.5
1.0
9.5
1.0
0.4
5.5
13.5
0.5
0.5
0.2
Car-mine
[%]
Bril-liantBlue[%]
0.8
1.3
0.9
4.5
1.0
0.7
3.0
a) L* a* b*
Tablet
Recipe 1
Recipe 3
Recipe 2
89.9
88.1
89.7
90.4
8.2
9.2
6.9 16.9
DE
19.0
18.4
19.58.8
0.0
2.2
2.0
1.3
b) Kollicoat IR
White ||
Red
Yellow
Recipe 1
95.6
4
0.4
Recipe 2
96.7
3 2.9
96.7
Recipe 3
00.3
SunsetYellow
0 0.40
Delta
E
5.0
4.5
4.0
3.0
2.5
1.5
1.0
0.0
1 2 4 6 8 10
3.5
2.0
0.5
3 5 7 9
Kollicoat® IR
Excipients & Actives for Pharma
Page 15
No. 24, 2010
If you have ever had the task of cleaning aproduction-scale film coater, you are most prob-ably well aware of this problem: pigment residuesremaining in the tubes which carry the film coat-ing dispersion to the nozzle. With large-scalecoating equipment, this effect can be observedquite frequently, leading to a number of problemsduring the film coating process.
PROBLEM | The problem of deposition occur-ring in the tubing is not so much the loss of pig-ments, since the loss of material can be regardedas being comparatively low. However, the impacton the quality of the final product can be remark-ably high. Deposited pigments resistant to re-moval by rinsing the tubing with water can flakeoff the inner walls of the tubes and can causeclogging of the nozzle and/or produce spots onthe core surface by depositing pigment agglom-erates. Both factors may result in unacceptablequality of the tablets being coated.
The effect of sedimentation is described byStokes’s law (Equation 1), which states that thesedimentation velocity (vs) depends on the sizeof a given particle (dp), the difference between thedensities of the pigments (ρp) and the liquid car-rier (ρl), gravity (g) and viscosity (η).
A closer look at Stokes’s law indicates that thefilm-forming characteristics of the polymersshould also be taken into consideration. In a typ-ical instant-release coating formulation, the typeof polymer and its concentration mainly deter-mine the viscosity of the dispersion.
>
Trouble-Shooting in Film Coating: Deposition and SedimentationT. Cech, F. Wildschek
Figure 2 shows the dynamic viscosity of typicalwater-soluble instant release film coating poly-mers.
It can be seen that modern film formers likepolyvinyl alcohol (PVA), Kollicoat IR and KollicoatProtect have low viscosities. This enables the op-erator to use a high concentration of solid matterin the dispersion, thereby shortening the processtime. With regard to moisture-protective coatingswhen high amounts of solids and small amountsof polymer are recommended to optimize thebarrier effect, viscosity plays a crucial role1. If theviscosity is too low, a tendency towards strongersedimentation can be observed.Furthermore, polymeric dispersions such aswater-insoluble polymers emulsified in water (e.g.Kollicoat SR 30 D) are sensitive with regard tosedimentation; this is because the polymer doesnot dissolve in the liquid carrier and thereforedoes not contribute to increasing the viscosity.Sedimentation due to low viscosity can be
prevented in the vessel containing the dispersionby continuous stirring. However, stirring does notsolve the deposition issue in the tubing.
SOLUTION | According to Stokes’s law, particlesize (dp) to the power of two is the variable withthe highest impact on sedimentation. This highimpact of particle size on the sedimentation vel-ocity can be used for reducing the tendency tosediment by selecting finer particles which arenot as prone to quick deposition.
TROUBLE-SHOOTING – FILM COATING
FIGURE 2 Dynamic viscosity as a function of polymer content
EQUATION 1 Stokes´s law
TABLE 1 Characteristic values for talc and kaolin particles
Particle size
Specific density
10 - 20 µm
2.58 - 2.83 g/mL
0.5 - 1.0 µm
2.61 - 2.68 g/mL
Talc Kaolin
log
dyna
mic
visc
osity
[mPa
s]
10000
0
Polymer concentration [%]
HPMC 3 mPas HPMC 6 mPas HPC EF PVA Kollicoat IR Kollicoat Protect
1000
100
10
1
5 10 15 20 25
x
x
x
x
x
x
+
+
+
+
x +
V s =d2 ·p (ρp – ρl) · g
18 · η
Excipients & Actives for Pharma
Page 16
No. 24, 2010
FIGURE 3 PSD of film coating dispersions based on different polymers
One pigment used quite often in film coating for-mulations is talc. An alternative additive similar incharacteristics and fields of application but ofconsiderably smaller particle size is kaolin (Table1, Figures 3, 4 and 5).Comparing the particles size distribution (PSD) offilm coating dispersions containing either talc or
kaolin shows that kaolin shifts the PSD to smallervalues, thereby reducing the sedimentation ten-dency considerably (Figure 3). This is why this ex-cipient is used in BASF's ready-to-use coatings.Alternatively, a thickening agent can be used forpreventing sedimentation. A reduction in sedi-mentation can also be achieved by increasing
both the density of the liquid carrier and itsviscosity. However, the effect is less noticeableand increasing viscosity influences the coatingprocess itself, leading to longer process timesand negative effects such as bridging and orangepeel.
In any case, deposition cannot be avoidedcompletely. In view of this, we can make somepractical recommendations on how to limit sedi-mentation effects to a minimum:
� Use tubes with an inner diameter commen-surate with both spray rate and viscosity.
� Always keep the tubing as short as pos-sible.
� As sedimentation mainly occurs in areaswhere the tubing is horizontal, align the tub-ing preferably vertically.
� If sedimentation starts to occur, reduce theamount of deposited material at an earlystage by gently squeezing the tubing withyour fingers.
� Try to keep the pump running continuouslyand stop spraying only if really necessary,as, during movement, the degree of disper-sion sedimentation is always lower.
Taking all these points into account, undesiredproblems such as gun blockage, bridging or col-ored spots on the film-coated tablets can be sub-stantially reduced.
REFERENCES
[1] Agnese, T., Cech, T., Kolter, K.; Developingan instant release moisture protective coat-ing formulation based on Kollicoat Protect asfilm forming polymer; PBP World Meeting;April 7-10, 2008; Barcelona, Spain
[2] Kibbe, A. H.; Handbook of PharmaceuticalExcipients; Pharmaceutical Press; 2000;London, U.K.
|
Dist
ribut
ion
[%]
10
8
6
0
0.01 100
4
2
0.1 1 10 1000 10000
Log.particle size [µm]
Kaolin (Kollicoat® IR White)
Talc (HPMC-based)
Talc (PVA-based)
FIGURE 4 SEM of talc FIGURE 5 SEM of kaolin
Excipients & Actives for Pharma
Page 17
No. 24, 2010
PVP and its derivatives in pharmaceuticalproductionPVP - also known under the compendial name"povidone" - has a long tradition at BASF and isone of the most interesting and versatile poly-mers used in the pharmaceutical industry. It helpsmany of our customers to be even more success-ful.Under the registered trade name Kollidon®, PVPis mainly used in tablets as a binder and disinte-grant. It thus makes the tablet a true high-techproduct: as a binder, it enables the individual ac-tive ingredients of a tablet to form a homogenousentity and as a disintegrant it ensures that thetablets break up in liquid and release the activeingredient quickly.
Quality and patient safety with PVP from BASFRecently, BASF introduced a new plastic film as
>
PVP (polyvinylpyrrolidone): An All-Round Talent with TraditionC. Easterbrook, S. Hoefer
primary packaging and BASF has applied for apatent regarding this new packaging system. Thisfilm is designed to protect BASF’s pharmaceuti-cal excipient polyvinylpyrrolidone (PVP) even bet-ter against atmospheric oxygen and thus againstoxidation. This new and innovative packagingraises product quality and thus improves patientsafety.
The highest possible quality standards are re-quired for pharmaceutical applications. BASF’sproducts, processes and facilities in fact exceedthe strict international quality standards of thepharmaceutical industry. Consequently, theUnited States Pharmacopeia (USP), an independ-ent work of reference, has certified the PVP pro-duced by BASF. Prior to certification, the USPchecked not only compliance with the require-ments of current Good Manufacturing Practice(cGMP), but also the quality and the documenta-tion of production and quality control. At thesame time, the PVP marketed by BASF was alsocertified for the European market subsequent toa wide-ranging GMP audit. BASF guarantees aconsistently high product quality and in this waycontributes to the success of its pharmaceuticalcustomers. Recently, International Pharmaceuti-cal Excipients Auditing (IPEA) confirmed theexcellent quality of BASF’s PVP pharma grades.BASF as well as other established PVP manufac-turers fulfill all requirements of the relevantcompendia. Read more on the importance of
adequate supplier qualification in “Pharmaceuti-cal Technology” Volume 33 No. 10 pp. 84-88 (Oc-tober 2009). The information is also accessibleunder www.kollidon.de.
70 years of tradition in PVP productionPVP is a product that has been a real successstory. About 70 years ago, at the beginning of1939, the chemist Walter Reppe, working in aBASF laboratory in Ludwigshafen, patentedthe production process for the polymerpolyvinylpyrrolidone. It quickly became clear thatthe BASF researcher had discovered a veritableall-rounder: PVP, although soluble in water, canalso absorb large quantities of water. It is non-irritating to the skin and does not pose a healthhazard. It is also temperature-resistant, pH-stable,non-ionic and colorless. Due to these varied fea-tures, PVP can be used in a wide range of applica-tions. Even today, new opportunities continue tobe found. This makes PVP an all-round talent thathas a firm place in the BASF product portfolio. |
ENDURING QUALITY
BASF's new and innova-tive packaging raisesproduct quality and thusimproves patient safety.
Library picture featuring old packaging
Excipients & Actives for Pharma
Page 18
No. 24, 2010
� Certificates of suitability – a benefit forour customersAs a manufacturer of active ingredients andexcipients, BASF has applied for certifi-cates concerning the evaluation of the suit-ability of the monograph for the control ofthe chemical purity and microbiologicalquality of the substances – the CEP. Thecertification procedure was established in1994. To date BASF holds more than 30CEPs, guaranteeing the quality of theiractive ingredients and confirming that thesesubstances comply with the European Phar-macopoeia and hence the requirements ofEU Directives for medicines.CEPs are recognized by all Member Statesof the European Pharmacopoeia Conven-tion as well as by other countries such asCanada, Australia, New Zealand, Tunisiaand Morocco.The CEP facilitates the management of ourcustomers’ applications for Marketing Au-thorization for drugs in all these countries.A retest period mentioned on the CEP
means that the results of stability studieshave been supplied to and assessed by theEDQM, the European Directorate for theQuality of Medicines & HealthCare, respon-sible for the evaluation of CEP applications.As a reliable partner to the pharmaceuticalindustry, BASF continuously carries out sta-bility studies for all its APIs and excipientsin accordance with relevant ICH Guidelines.Through the submission of complementaryand additional stability data, the retest pe-riod of many products could be extendedover the past year – a benefit for pharma-ceutical companies and a further step tohelp our customers to be even more suc-cessful.
� New US DMF Kollicoat® IR CoatingSystems, DMF #23187BASF has developed colored coating sys-tems for instant-release film-coating basedon Kollicoat IR, a water-soluble film formerfor the instant-release coating of pharma-ceutical dosage forms. BASF offers seven
New BASF CEPs with an extended retested period
basic colors, which can be combined toachieve a wide variety of different colorshades. To support the formulation, devel-opment software has been programmed topredict the blend of basic colors required toachieve the desired color shade.
� New US DMF phenylephrinehydrochloride, DMF #23083Phenylephrine is an effective decongestantfor treating allergic and cold indications.With the launch of this well-established sub-stance, BASF is further extending its APIportfolio. As it is produced under cGMPconditions, BASF is focusing on reliable andconsistent product quality in line with thehighest international quality standards.
� Soluplus®
A Type IV DMF containing information onchemistry, manufacture and control hasbeen filed with the FDA. DMF number as-signed: #23504. A Type V DMF containingpre-clinical safety information has also beenfiled. DMF number assigned: #23626.
� Solutol® HS 15In addition to the Type IV DMF (#9501)which is already available, a Type V DMFcontaining pre-clinical safety informationhas been filed with the FDA. DMF numberassigned: #23531. A Solutol HS 15 mono-graph titled "Polyoxyl 15 hydroxystearate”will be published in USP 33-NF 28, whichbecomes official as of October 2010.Solutol HS 15 is a solubilizer for hardly sol-uble APIs. Solubility is a prerequisite forBCS class 2 and class 4 chemical entities tobe successfully formulated into pharmaceu-tical dosage forms. Although no FDA-regis-tered formulations and thus marketapprovals for finished medicinal productscontaining Solutol HS 15 exist on the US
UPDATE ON REGULATORYAFFAIRS
D. C. Kriha, C. Becker
Substance CEP # New retestperiod
[months]
Monograph #(Ph. Eur.)
Aminophylline anhydrous/Theophylline-ethylenediamine
Aminophylline hydrous/Theophylline-ethylenediamine hydrate
Caffeine
Dobutamine hydrochloride
Tilidine hydrochloride hemihydrate
Xylometazoline hydrochloride
Dopamine hydrochloride
Oxymetazoline hydrochloride
2007-288
2007-289
1998-022
2007-049
2006-273
2008-064
2007-045
2006-286
18
18
60
18
60
36
36
48
300
301
267
664
1200
943
1767
1162
Excipients & Actives for Pharma
Page 19
No. 24, 2010
Kollicoat IR Coating SystemsNow everyone can create their own color simplyand cost-effectively. This new ready-to-use sys-tem for colored coatings makes the productionof tablet coatings faster, more flexible, and morerobust than ever before. Kollicoat IR Coating Sys-tems have excellent flow properties and can bere-dispersed quickly and easily. The seven glo-
Kollicoat® IR Coating SystemsCreate Your Own Colors.
Pharma Ingredients & Services. Welcome to more opportunities.Custom Synthesis | Excipients | Active Ingredients
Dr. Thorsten Schmelleran enabler in excipients
Soluplus® – The Solid SolutionOpening New Doors in Solubilization.
Pharma Ingredients & Services. Welcome to more opportunities. Excipients
Dr. Shaukat Ali, an enabler in excipients
NEW MARKETING ASSETS
market, the monograph was developed andapproved. This was driven by the Novel Ex-cipient Safety Evaluation Procedure thatIPEC Americas developed with input fromthe FDA, clinical trial data from Wyeth andsafety evidence from BASF.
� Kollicoat IRA revised draft EP Monograph “MacrogolPoly (vinyl alcohol) grafted copolymer” willbe published in the next Pharmeuropa. Inthe meantime, the monograph in Supple-ment 6.7 remains valid. USP-NF mono-graph “Ethylene Glycol and PolyvinylAlcohol Graft Copolymer” is included in theFirst Supplement to USP 33-NF 28, whichbecomes official as of October 2010.A draft JPE monograph (harmonized with
the upcoming EP/USP-NF monographs) isunder preparation.
� Kollicoat MAE 100 PA USP/NF monograph "Partially-NeutralizedMethacrylic Acid and Ethyl Acrylate Copoly-mer" is adopted into the Second Supple-ment to USP 33-NF 28, which becomesofficial as of February 2011.
� Kollicoat SR 30 DA new monograph for Kollicoat SR 30 D en-titled "Polyvinylacetate Dispersion" will bepublished in the 2010 USP 33/NF28 edition.Kollicoat SR 30 D is an aqueous polyinylacetate dispersion that was developed forsustained release applications, where theactive ingredient is released independently
of the pH-value. It can be used as a filmcoating agent and as a wet binder for matrixtablets. A monograph for Kollicoat SR 30 Dis also included in the European Pharma-copoeia ("Poly(Vinyl Aceteate) Dispersion 30Per Cent" #2152).
� AmylmetacresolAmylmetacresol is a local antiseptic used totreat minor infections of the mouth andthroat. OTC products containing amyl-metacresol are registered worldwide. Thedraft EP monograph prepared by BASF incollaboration with the EDQM has beenadopted by the European PharmacopoeiaCommission, and becomes official in thenext supplement to EP. A CEP application isalready under preparation.
bally approved base colors can be combined tocreate hundreds of shades. To download thisbrochure, please use this link:www.coating-systems.basf.com
Soluplus – The Solid SolutionThis pioneering product overcomes the problemof poorly soluble active ingredients and bringsbioavailability to a new level. Soluplus is unique inmany ways. Thanks to its high flowability andexcellent extrudability, Soluplus shows superiorperformance in forming solid solutions, especiallyin hot melt extrusion processes. It makes theactive pharmaceutical ingredient (API) availablein a dissolved state, resulting in improved bio-availability once in the body. But that’s not all.A comprehensive range of toxicological datademonstrates the product’s safety. To downloadthis brochure, use the following link:www.soluplus.com
Excipients & Actives for Pharma
July 10-14, 2010The 37th Annual Meeting and Expositionof the Controlled Release SocietyPortland, Oregon, USA
October 5-7, 2010CPhI WorldwideParis Nord VillepinteParis, France
November 14-18, 2010AAPS Annual Meeting and ExpositionNew Orleans, Louisiana, USA
December 1-3, 2010CPhI IndiaBombay Exibition CentreMumbai, India
Our next Trouble-Shooting column will bring an interesting and helpful study on plasticizers used in filmcoating formulations. Since plasticizers play a decisive role in the application of functional coats, it isessential to have reliable recommendations for formulators.The choice of a suitable plasticizer shows positive effects on the relevant processing properties of thepolymer, such as flexibility and minimum film forming temperature. Look out for this article in our nextedition and learn more about plasticizers application in film coating formulations!
What opportunities can we open up for you?Would you like to discuss a particular challenge or product in more detail? Or do you have anyquestions? Simply call or e-mail us. We would be glad to help.
AsiaBASF East Asia RegionalPharma Ingredients & ServicesThomas Pilgram45th Floor, Jardine House,No. 1 Connaught Place,Central, Hong KongPhone: +852 [email protected]
EuropeBASF SEPharma Ingredients & ServicesPeter HoffmannG-EMP/EM – J 55067056 LudwigshafenGermanyPhone: +49 621 [email protected]
North AmericaBASF CorporationPharma Ingredients & ServicesNigel Langley, Ph.D., MBA540 White Plains RoadTarrytown, NY, USA10591-9005Phone: +1 914 785 [email protected]
South AmericaBASF S.A.Pharma Ingredients & ServicesFlavia de Assis e SouzaS-EM/VPPAvenida Faria Lima, 3600 – 9th floor04538-132 São Paulo – SP BrazilPhone: +55 11 [email protected]
CALENDAR PREVIEW
CONTACT
EMP040102e-24
Influence of Various Plasticizers on theProperties of a Kollicoat® SR 30 D-BasedCoating
Excipients & Actives for Pharma No. 24, 2010
