Kollidon® CLKollidon® CL-FKollidon® CL-SFKollidon® CL-MSuper-disintegrants and dissolution enhancers.
The Preface2
Trademarks are owned by BASF Aktiengesellschaft
The disintegration of a tablet can be regarded as the initial step in terms of bioavailability and phar-macological action of the active substance. To achieve rapid disin-tegration, a disintegrant normally has to be added to the tablet for-mulation. The insoluble grades of Kollidon® are widely used in the pharmaceuticals industry for this purpose. Furthermore, their use as pharmaceutical excipients is
triggered by their ability to hydro-philize insoluble drugs, to stabilize suspensions and to form com-plexes, as well as by their adsorp-tive properties.
BASF supplies Kollidon® CL, Kollidon® CL-F and Kollidon® CL-SF as disintegrants for the pharmaceutical industry. Kollidon® CL-M is usually used as a suspension stabilizer.
New: 4 dimensions of Kollidon® CL – standard,
fi ne (CL-F), superfi ne (CL-SF) and micronized (CL-M) for
your individual needs. Kollidon® is well known as a
universal excipient range since more than 60 years.
Kollidon® CL, the cross-linked PVP, is not only one of
the three “super-disintegrants”. Moreover, Kollidon® CL accel-erates the dissolution and thebioavailability due to its power to form complexes with many
insoluble actives.
time [min]
dis
solv
ed d
rug
[%
]
+ 3 % Kollidon® CL
100
90
80
70
60
50
40
30
20
10
0
0 10 20 30 40 50 60
without Kollidon® CL
Dissolution of acetylsalicylic acid tablets
The Preface 3
Over the past few years, there has been a trend towards highly potent actives (HPAPI) and, as a consequence, a trend towards smaller tablets. The growth rate of 19 % for HPAPIs underlines the strong market need for po-tent disintegrants for these ap-plications. These smaller tablets usually require disintegrants of much smaller particle size to guarantee content uniformity and to prevent the tablets from show-
ing rough surfaces after storage. The disintegrants, however, still require the power suffi cient for a rapid disintegration. Scientifi c in-vestigation has indicated that the disintegration power decreases with decreasing particle size. This can be confi rmed by testing our new materials Kollidon® CL-F and Kollidon® CL-SF. Although these materials have smaller particle sizes, they are still potent disinte-grants.
Furthermore, in new drug delivery technologies such as oral dispers-ible tablets, fast disintegrants with very good mouth feeling are in strong demand. Many of these drugs go into pediatric applications and to the OTC market in general, where good patient compliance is a precondition for the success of a drug formulation. Based on these market trends, our customers will now require new disintegrants for their new applications.
The theory of disintegration of a tablet
1. Disintegrants are very hydrophilic.
2. Spherical particles are uniformly distributed in the tablet.
3. They swell during contact with water or other liquids.
4. They signifi cantly increase volume and disintegrate the tablet.
water
The Market Trends
water
water
The Products4
The different Kollidon® CL grades can best be distinguished by their different particle sizes:
Average particle size range [µm]
■ Kollidon® CL 110–130■ Kollidon® CL-F 20–40■ Kollidon® CL-SF 10–30■ Kollidon® CL-M 3–10
All CL-grades are crosslinked, wa-ter-insoluble polivinylpyrrolidones. There are chemical but mainly physical crosslinks.
Chemical names
■ Crospovidone■ Crospovidonum■ Insoluble polyvinylpyrrolidone■ Crosslinked PVP
In contrast to many other disinte-grants, the Kollidon® CL grades are non-water-soluble. As a conse-quence, there is no infl uence on the disintegration of a tablet and the dissolution of the active due to the increased viscosity. The cros-povidones act as disintegrants by absorbing water and subsequently swelling. This gain in volume is responsible for the subsequent disintegration of the tablet.
However, the speed of disinte-gration is not only based on the swelling;
it is a combination of many factors such as:
■ The swelling volume of the disintegrant■ The swelling pressure of the disintegrant■ The hydrophilic behavior of the disintegrant ■ The pore sizes within the tablet■ The mechanical properties of the tablet
The chemical structure of Kollidon® CL: It is a cross-
linked homopolymer of N-vinyl-2-pyrrolidone
Chemical crosslinks
Entangled polymer chains (N-vinylpyrro-lidone-polymer)
A highly (mainly physically) crosslinked polymer matrix
*n
O
N
*
6 The Application
In general, there is no perfect disintegrant. Disintegration is
strongly dependent on the for-mulation of the tablet in terms
of porosity, method of manu-facture (wet or dry granula-
tion) and the use of different actives and other excipients.
Even with a decreased particle size, the new grades Kollidon® CL-F and Kollidon® CL-SF show good performance, not having some of the drawbacks that Kolli-don® CL has, as explained above.
Apart from the increase in tablet disintegration, it is even more im-portant that the dissolution of the active ingredient is also increased.
Comparison of the materials
The principle property of the materials is to decrease the dis-integration time of tablets. In the fi gure below the three Kollidon grades are compared with their main competitive materials. Clearly, Kollidon® CL shows the strongest performance.
Disintegration time of direct compressed tablets with different disintegrants (6 % disintegrant in Ludipress® LCE, compressed at 18 kN)
Kollidon® CL
02:09
01:55
01:40
01:26
01:12
00:57
00:43
00:28
00:14
00:00
Kollidon® CL-F
Kollidon® CL-SF
Crospovi-done
Competitor A (100–130 µm)
Sodiumstarch
glycolate
Crospovi-done
Competitor A (30–50 µm)
tim
e [m
in:s
ec]
Croscar-mellose-sodium
7The Application
The dissolution curves show that Kollidon® CL has the best per-formance, followed by Kollidon® CL-F and Kollidon® CL-SF. In some cases customers may wish to have a slightly slower disinte-gration for specifi c applications; the new materials could help to produce a dissolution profi le fi tted to such a requirement, e. g. for generics.
A requirement of many customers is that the tablets show a smooth surface after storage in multidose containers. Because the Kollidon® CL grades are very hydrophilic, they tend to absorb water and thus produce a rough surface due to swelling. In the case of fi lm tablets, this might cause cracks in the fi lm. Tablets produced with fi ne materials Kollidon® CL-F and Kollidon® CL-SF produce a very smooth surface.
Dissolution of acetaminophen in deionized water (2.7 % disintegrant in a wet granulated formulation, compressed at 18 kN)
time [min]
dru
g r
elea
se [
%]
90
80
70
60
50
40
30
20
10
0
0 20 40 60 80 100 12010 30 50 70 90 110
100
■ Kollidon® CL■ Kollidon® CL-F■ Kollidon® CL-SF■ Crospovidone Competitor A (100–130 µm)■ Croscarmellose-sodium■ Crospovidone Competitor A (30–50 µm)■ Sodium starch glycolate
method: paddle 100 rpm; 37 °C
8 The ApplicationKollidon® CL
Kollidon® CL
Kollidon® CL is used as the stan-dard disintegrant for all kinds of fast dispersible tablet formulations. For many years, companies have known just how well the material performs. The main reasons for using Kollidon® CL are the ad-vantages provided compared to other materials like e. g. starch or cellulose derivatives. When used as disintegrants, these products tend to form highly viscous systems when in contact with water.
This is in contrast to Kollidon® CL, which is insoluble and which as a consequence does not slow down the dissolution of a oral dosage form but might even increase the release of the active ingredient. In some cases where Kollidon® CL does not meet the requirements of the customers e. g. for wet granu-lation with a large amount of sol-vent, Kollidon® CL-F or Kollidon® CL-SF are suitable replacements.
Kollidon® CL
. . . . . . . . . .50 µm
. . . . . . . . . .300 µm
. . . . . . . . . .10 µm
9The ApplicationKollidon® CL-F
Kollidon® CL-F
Kollidon® CL-F is the perfect alternative when formulators are looking for a disintegrant with strong disintegration power in combination with a smooth tablet surface. With Kollidon® CL, however, some problems might occur when the tablet is very hygroscopic and packed in a multi-dose container.
Kollidon® CL-F should be used for the development of small tablets when fi ne particles are required to avoid content uniformity prob-lems. Furthermore, the material is able to absorb large amounts of solvent. This can be benefi cial when customers use such large amounts during a wet granulation
step where large amounts of solvent are needed e. g. for dissolving the active.
However, in some cases, Kollidon® CL-SF might be the best solution for a specifi c application.
5.2 mm
8.5 mm
14.1
mm
23.5
mm
Capsules fi lled with microtablets (capsule size 00–4)
Microtablets,2 mm diameter
Kollidon® CL-F
. . . . . . . . . .300 µm
. . . . . . . . . .50 µm
. . . . . . . . . .10 µm
The Application Kollidon® CL-SF
10
Kollidon® CL-SF
Kollidon® CL-SF has advantages when it comes to special appli-cations, for example oral fast dis-persible tablets. The main reason is reliable disintegration power in combination with a very smooth cream-like mouth feel. Neverthe-less, in some cases, Kollidon®
CL-SF might be used as a regular disintegrant when customers have a wet granulation process that uses large amounts of solvent. Kollidon® CL-SF has the highest solvent (water/ethanol etc.) uptake capacity of all the crospovidones produced by BASF.
Kollidon® CL-SF
. . . . . . . . . .50 µm
. . . . . . . . . .10 µm
. . . . . . . . . .300 µm
12 The Examples
Formulation of Haloperidol tablets (direct tabletting)
Haloperidol 2 mg (2.5 %)Ludipress® LCE 75 mg (93.75 %)Kollidon® CL 2.5 mg (3.12 %)Magnesium stearate 0.5 mg (0.63 %)
Tablet weight 80 mg (100 %)
Formulation of Nifedipine tablets (granulated)
Nifedipine 10 mg (5.85 %)Kollidon® VA 64 10 mg (5.85 %)Ludipress® LCE 100 mg (58.50 %)Kollidon® CL-F or -SF 50 mg (29.22 %)Magnesium stearate 1 mg (0.58 %)
Tablet weight 171 mg (100 %)
13
As far as disintegrants are con-cerned, there are many products in the market starting with the basic starches derived from maize, rice, corn and potato. They have been used for a long time but have certain disadvantages in terms of the amount that is needed to
The Overview
ensure disintegration. One particu-lar disadvantage of disintegrants based on starch and of the cellu-lose derivatives is the increase of viscosity after disintegration. The fi rst question is always related to the real effect of the disintegrant on the disintegration time.
In the fi gure, the disintegration test results of tablets produced with granulated material are shown. These clearly show the strengths of the crospovidones, especially the Kollidon® CL grades.
Kollidon® CL
35
30
25
20
15
10
5
0Kollidon®
CL-FKollidon®
CL-SF
dis
inte
gra
tio
n ti
me
[min
]
Kollidon® CL-M
Disintegration of tablets made of granules (2,7 % disintegrant extragranular use, compressed at 18 kN)
11:0809:06
12:46 12:30
22:37 23:28
33:56
Crospovi-done
Competitor A (100–130 µm)
Sodiumstarch
glycolate
Crospovi-done
Competitor A (30–50 µm)
Croscar-mellose-sodium
08:55
The Overview14
Disintegrants on the market
*: Not tested
Starches
Starch derivatives
Sodium starch glycolate
Cellulose derivatives
Carmellose-sodium
Croscarmellose-sodium
Carmellose-calcium
HPC
Crospovidone grades
Compet. A (100–130 µm)
Compet. A (30–50 µm)
Kollidon® CL
Kollidon® CL-F
Kollidon® CL-SF
Required Disinte- Hardness Issues during % gration power of the tablets storage at 1: low high humidity 10: high
3–15 3 Low *
2–8 4 High Brown spots
1–6 5 Medium *
0.5–5 7 High Brown spots (most cases 2–3)
5–15 5 Medium *
5–25 5 High *
2–5 8 High Rough surface
2–5 7 High Smooth surface
2–5 9 Medium Rough surface
2–5 8 High Smooth surface
2–5 7 Very high Smooth surface
The Summary 15
The following table describes the advantages of each material for our customers – the pharma-
ceutical industry and their customers, the patients.
Depending on the preferred disintegration and dissolution rate, our customers can select the excipient of choice from our comprehensive product range.
Kollidon® CL
Kollidon® CL-F
Kollidon® CL-SF
Kollidon® CL-M
Benefi ts for manufacturers Benefi ts for patients Main applications
The super-disintegrant, Fast drug absorption Disintegrant for very fast disintegration for most APIs standard tablets
No content uniformity Easy to swallow Small tablets, problems especially in due to tablet size tablets stored under small tablets high humidity Perfect for fast Best mouthfeel Fast dispersible dispersible tablets, tablets, excellent tablet surface intragranular disintegrant for wet granulation
Stable dispersions Easy to redisperse Suspensions
BASF AktiengesellschaftG-MEP/ME – Li 554Attn: Dr. Hubertus FolttmannCarl-Bosch-Straße 64D-67117 LimburgerhofGermany
Please send the following information:
■ Technical information on Kollidon® CL grades.
■ Sample of Kollidon® CL, 0.5 kg.■ Sample of Kollidon® CL-F, 0.5 kg.■ Sample of Kollidon® CL-SF, 0.2 kg.■ Sample of Kollidon® CL-M, 0.5 kg.
■ Please contact me, I would like to know more about Kollidon® CL.
■ Technical information on Kollidon® VA 64.
■ Technical information on Kollidon® VA 64 Fine.
■ Technical information on Ludipress®.
■ DVD “Pharmaceutical Excipients by BASF Fine Chemicals”.
■ Newsletter “ExAct” (Excipients & Actives for Pharma).
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AsiaBASF Asia Pacifi c Regional HQPharma Solutions Dr. Danilo MercadoBASF East Asia Regional Headquarters Ltd.45th Floor, Jardine House,No.1 Connaught Place,Central, Hong KongPhone: +852-27311-588Fax.: [email protected]
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Please contact your local BASF company or one of the following regional centers:
EuropeBASF AktiengesellschaftMEE/HP – J 550 Mr. Peter HoffmannD-67056 LudwigshafenGermanyPhone: +49-621-60-7 69 28Fax: +49-621-60-7 69 [email protected]
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Please send the following information:
■ Technical information on Kollidon® CL grades.
■ Sample of Kollidon® CL, 0.5 kg.■ Sample of Kollidon® CL-F, 0.5 kg.■ Sample of Kollidon® CL-SF, 0.2 kg.■ Sample of Kollidon® CL-M, 0.5 kg.
■ Please contact me, I would like to know more about Kollidon® CL.
■ Technical information on Kollidon® VA 64.
■ Technical information on Kollidon® VA 64 Fine.
■ Technical information on Ludipress®.
■ DVD “Pharmaceutical Excipients by BASF Fine Chemicals”.
■ Newsletter “ExAct” (Excipients & Actives for Pharma).
BASF – the world’s leading chemical company – can look back on well over 140 years of success and has attained an outstanding position as a reliable partner.
Our portfolio for the pharmaceutical industry comprises a comprehensive range of major and new active ingredients and excipient brands.
■ ExcipientsKollidon® gradesGroup of povidone and copovidone products suitable mainly as tablet binders, crospovidone as tablet disintegrant and dissolution enhancer.Kollidon® SRMatrix sustained release polymer.Ludipress® gradesDirect tabletting aids for faster product develop-ment and speedier processing. Kollicoat® gradesRange of aqueous based fi lm formers, cost effi cient and ecological.
Cremophor® grades and Solutol® HS 15Range of different ethoxylated emulsifi ers and solubilizers suitable for topical, oral and parenteral formulations. Soluphor® P2-pyrrolidone.Lutrol® gradesRange of PEGs (Lutrol® E range) and poloxamers (Lutrol® F range) for a wide variety of pharmaceutical dosage forms.
■ ActivesEphedrinesPseudoephedrinesTheophyllineCaffeineIsotretinoinTretinoinIbuprofenDobutamineDopamineIsometheptene mucateOxymetazolinePVP-IodineSelegilineXylometazoline
APIs by Orgamol
Vitamins
■ Contract Manufacturing
■ Value Added
ME
MP
06
04
01
e-0
0
BASF offers more than cGMP quality and supply safety: technical expertise. Our technical service is always at your side. BASF wishes to create a prosperous and sustain-able future with you as our customer – and partner.
BASF AktiengesellschaftFine Chemicals DivisionPharma Solutions67056 LudwigshafenGermany
■ Fax +49-621-60-2 86 40■ [email protected]■ www.pharma-solutions.basf.com
Pharma Solutions by BASF