Kollidon CL Kollidon CL-F Kollidon CL-SF Kollidon CL-M. Super-disintegrants and dissolution enhancers.

Transcription

1 Kollidon CL Kollidon CL-F Kollidon CL-SF Kollidon CL-M Super-disintegrants and dissolution enhancers.

2 2 The Preface New: 4 dimensions of Kollidon CL standard, fine (CL-F), superfine (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 crosslinked PVP, is not only one of the three super-disintegrants. Moreover, Kollidon CL accelerates the dissolution and the bioavailability due to its power to form complexes with many insoluble actives. The disintegration of a tablet can be regarded as the initial step in terms of bioavailability and pharmacological action of the active substance. To achieve rapid disintegration, a disintegrant normally has to be added to the tablet formulation. 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 hydrophilize insoluble drugs, to stabilize suspensions and to form complexes, as well as by their adsorptive 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. Trademarks are owned by BASF Aktiengesellschaft Dissolution of acetylsalicylic acid tablets dissolved drug [%] % Kollidon CL without Kollidon CL time [min]

3 The Preface 3 The theory of disintegration of a tablet 1. Disintegrants are very hydrophilic. water 2. Spherical particles are uniformly distributed in the tablet. water 3. They swell during contact with water or other liquids. water 4. They significantly increase volume and disintegrate the tablet. The Market Trends 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 potent disintegrants for these applications. These smaller tablets usually require disintegrants of much smaller particle size to guarantee content uniformity and to prevent the tablets from showing rough surfaces after storage. The disintegrants, however, still require the power sufficient for a rapid disintegration. Scientific investigation has indicated that the disintegration power decreases with decreasing particle size. This can be confirmed by testing our new materials Kollidon CL-F and Kollidon CL-SF. Although these materials have smaller particle sizes, they are still potent disintegrants. Furthermore, in new drug delivery technologies such as oral dispersible 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.

4 4 The Products The different Kollidon CL grades can best be distinguished by their different particle sizes: Average particle size range [µm] Kollidon CL Kollidon CL-F Kollidon CL-SF Kollidon CL-M 3 10 All CL-grades are crosslinked, water-insoluble polivinylpyrrolidones. There are chemical but mainly physical crosslinks. In contrast to many other disintegrants, the Kollidon CL grades are non-water-soluble. As a consequence, there is no influence on the disintegration of a tablet and the dissolution of the active due to the increased viscosity. The crospovidones 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 disintegration is not only based on the swelling; * N n * O Chemical names Crospovidone Crospovidonum Insoluble polyvinylpyrrolidone Crosslinked PVP 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 Chemical crosslinks Entangled polymer chains (N-vinylpyrrolidone-polymer) A highly (mainly physically) crosslinked polymer matrix The chemical structure of Kollidon CL: It is a crosslinked homopolymer of N-vinyl-2-pyrrolidone

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6 6 The Application In general, there is no perfect disintegrant. Disintegration is strongly dependent on the formulation of the tablet in terms of porosity, method of manufacture (wet or dry granulation) and the use of different actives and other excipients. Comparison of the materials The principle property of the materials is to decrease the disintegration time of tablets. In the figure below the three Kollidon grades are compared with their main competitive materials. Clearly, Kollidon CL shows the strongest performance. 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 Kollidon CL has, as explained above. Apart from the increase in tablet disintegration, it is even more important that the dissolution of the active ingredient is also increased. Disintegration time of direct compressed tablets with different disintegrants (6 % disintegrant in Ludipress LCE, compressed at 18 kn) 02:09 01:55 01:40 time [min:sec] 01:26 01:12 00:57 00:43 00:28 00:14 00:00 Kollidon CL Kollidon CL-F Kollidon CL-SF Crospovidone Competitor A ( µm) Crospovidone Competitor A (30 50 µm) Croscarmellosesodium Sodium starch glycolate

7 The Application 7 Dissolution of acetaminophen in deionized water (2.7 % disintegrant in a wet granulated formulation, compressed at 18 kn) 100 method: paddle 100 rpm; 37 C drug release [%] Kollidon CL Kollidon CL-F Kollidon CL-SF Crospovidone Competitor A ( µm) Croscarmellose-sodium Crospovidone Competitor A (30 50 µm) Sodium starch glycolate time [min] The dissolution curves show that Kollidon CL has the best performance, followed by Kollidon CL-F and Kollidon CL-SF. In some cases customers may wish to have a slightly slower disintegration for specific applications; the new materials could help to produce a dissolution profile fitted 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 film tablets, this might cause cracks in the film. Tablets produced with fine materials Kollidon CL-F and Kollidon CL- SF produce a very smooth surface.

8 8 The Application Kollidon CL Kollidon CL Kollidon CL is used as the standard 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 advantages 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 granulation with a large amount of solvent, Kollidon CL-F or Kollidon CL-SF are suitable replacements µm µm µm Kollidon CL

9 The Application Kollidon CL-F 9 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. Capsules filled with microtablets (capsule size 00 4) 23.5 mm 8.5 mm 5.2 mm 14.1 mm µm µm µm Kollidon CL-F Kollidon CL-F should be used for the development of small tablets when fine particles are required to avoid content uniformity problems. Furthermore, the material is able to absorb large amounts of solvent. This can be beneficial 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 specific application. Microtablets, 2 mm diameter

10 10 The Application Kollidon CL-SF Kollidon CL-SF Kollidon CL-SF has advantages when it comes to special applications, for example oral fast dispersible tablets. The main reason is reliable disintegration power in combination with a very smooth cream-like mouth feel. Nevertheless, 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 µm Kollidon CL-SF µm µm

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12 12 The Examples Formulation of Nifedipine tablets (granulated) Nifedipine 10 mg (5.85 %) Kollidon VA 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 %) 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 %)

13 The Overview 13 As far as disintegrants are concerned, 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 ensure disintegration. One particular disadvantage of disintegrants based on starch and of the cellulose derivatives is the increase of viscosity after disintegration. The first question is always related to the real effect of the disintegrant on the disintegration time. In the figure, 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. Disintegration of tablets made of granules (2,7 % disintegrant extragranular use, compressed at 18 kn) :56 disintegration time [min] :55 Kollidon CL 11:08 Kollidon CL-F 09:06 Kollidon CL-SF 12:46 12:30 Kollidon CL-M Crospovidone Competitor A ( µm) 22:37 Crospovidone Competitor A (30 50 µm) 23:28 Croscarmellosesodium Sodium starch glycolate

14 14 The Overview Disintegrants on the market Required Disinte- Hardness Issues during % gration power of the tablets storage at 1: low high humidity 10: high Starches Low * Starch derivatives Sodium starch glycolate High Brown spots Cellulose derivatives Carmellose-sodium Croscarmellose-sodium Carmellose-calcium HPC Medium * High Brown spots (most cases 2 3) Medium * High * Crospovidone grades Compet. A ( µm) Compet. A (30 50 µm) Kollidon CL Kollidon CL-F Kollidon CL-SF High Rough surface High Smooth surface Medium Rough surface High Smooth surface Very high Smooth surface *: Not tested

15 The Summary 15 The following table describes the advantages of each material for our customers the pharmaceutical industry and their customers, the patients. Benefits for manufacturers Benefits for patients Main applications Kollidon CL The super-disintegrant, Fast drug absorption Disintegrant for very fast disintegration for most APIs standard tablets Kollidon CL-F No content uniformity Easy to swallow Small tablets, problems especially in due to tablet size tablets stored under small tablets high humidity Kollidon CL-SF Perfect for fast Best mouthfeel Fast dispersible dispersible tablets, tablets, excellent tablet surface intragranular disintegrant for wet granulation Kollidon CL-M Stable dispersions Easy to redisperse Suspensions Depending on the preferred disintegration and dissolution rate, our customers can select the excipient of choice from our comprehensive product range.

16 Please write in block letters. Thank you. Title/Name Department Please apply postage stamp. Company Address Town Country Telephone Fax Reply card BASF Aktiengesellschaft G-MEP/ME Li 554 Attn: Dr. Hubertus Folttmann Carl-Bosch-Straße 64 D Limburgerhof Germany Fax Reply Local contact: or Headquarter Germany: Please complete, copy and fax to us, or detach the postcard and send it to us. 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. 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). Please contact me, I would like to know more about Kollidon CL.

17 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. 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). Please contact me, I would like to know more about Kollidon CL. We look forward to answering any questions you may have. Please fill in the postcard, detach it and return it to the address overleaf. Please contact your local BASF company or one of the following regional centers: Asia BASF Asia Pacific Regional HQ Pharma Solutions Dr. Danilo Mercado BASF East Asia Regional Headquarters Ltd. 45th Floor, Jardine House, No.1 Connaught Place, Central, Hong Kong Phone: Fax.: mercadd@ basf-east-asia.com.hk Europe BASF Aktiengesellschaft MEE/HP J 550 Mr. Peter Hoffmann D Ludwigshafen Germany Phone: Fax: peter.01.hoffmann@ basf.com North America BASF Corporation Pharma Solutions Mr. Javier Beeck 100 Campus Drive Florham Park, NJ USA Phone: Fax: javier.beeck@ basf.com South America BASF S.A. Human Fine Chemicals Ms. Vanessa Occhipinti Estrada Samuel Aizemberg, São Bernardo do Campo SP Brazil Phone: Fax: vanessa.occhipinti@ basf.com

18 Excipients Kollidon grades Group of povidone and copovidone products suitable mainly as tablet binders, crospovidone as tablet disintegrant and dissolution enhancer. Kollidon SR Matrix sustained release polymer. Ludipress grades Direct tabletting aids for faster product development and speedier processing. Kollicoat grades Range of aqueous based film formers, cost efficient and ecological. Cremophor grades and Solutol HS 15 Range of different ethoxylated emulsifiers and solubilizers suitable for topical, oral and parenteral formulations. Soluphor P 2-pyrrolidone. Lutrol grades Range of PEGs (Lutrol E range) and poloxamers (Lutrol F range) for a wide variety of pharmaceutical dosage forms. Actives Ephedrines Pseudoephedrines Theophylline Caffeine Isotretinoin Tretinoin Ibuprofen Dobutamine Dopamine Isometheptene mucate Oxymetazoline PVP-Iodine Selegiline Xylometazoline APIs by Orgamol Vitamins Contract Manufacturing Value Added Pharma Solutions by BASF 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 sustainable future with you as our customer and partner. BASF Aktiengesellschaft Fine Chemicals Division Pharma Solutions Ludwigshafen Germany Fax pharma.solutions@basf.com 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. MEMP e-00

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