Volker Bühler. Pharmaceutical Technology of BASF Excipients. Pharma Ingredients &Services. Welcome to more opportunities.

Transcription

1 Volker Bühler Pharmaceutical Technology of BASF Excipients Pharma Ingredients &Services. Welcome to more opportunities.

2 Volker Bühler Pharmaceutical Technology of BASF Excipients 3 rd revised edition June 2008

3 Contents Page Foreword 6 1. Instant-release solid dosage forms (Tablets, pellets, granules) 1.1 Binders General notes Binders for wet granulation Dry granulation (roller compaction) Direct compression Melt extrusion Disintegrants for normal tablets General notes Standard disintegrant: Kollidon CL Special disintegrants: Kollidon CL-F, Kollidon CL-SF Disintegrant for fast disintegrating buccal tablets Enhancers of drug release General notes Povidone: Soluble Kollidon grades Crospovidone: Kollidon CL grades Poloxamers Solubilizers: Cremophor RH Direct compression agents General notes Normal tablets with Ludipress Lozenges, chewable, effervescent and sustained-release tablets with Ludipress LCE Fast disintegrating tablets with Ludiflash Instant-release and protective coatings of tablets and capsules General notes Instant-release film-coating with Kollicoat IR Instant-release film-coating with Kollicoat IR White Protective film-coating with Kollicoat Protect Instant-release film-coating with Kollidon VA Traditional sugar coating Subcoatings of tablet cores Taste masking by coatings of tablets Taste masking by coatings of granules or crystals before tabletting Colorants (pigments) Modified-release solid dosage formes (Tablets, pellets, granules) 2.1 Enteric film-coatings General notes Enteric film-coating of tablets and capsules Enteric film-coating of pellets and crystals 66 2

4 2.2 Sustained-release pellets Coating with Kollicoat SR 30D Coating with Kollicoat EMM 30D Sustained-release tablet Direct compression with Kollidon SR Wet granulation and compression to matrix tablets Compression of sustained-release pellets Sustained-release film-coating of tablet cores with Kollicoat SR 30D Plasticizers Propylene glycol Macrogols Mucoadhesives for buccal tablets Soft gelatin capsules 3.1 Carriers, solvents Solubilizers Antioxidants Colorants Solutions 4.1 Solubilization for oral and topical use Surfactants: Cremophor RH 40, Cremophor EL Complex formers: Kollidon 25 and Kollidon Poloxamers: Lutrol F68 and Lutrol F Solubilization for parenteral use Complex formers: Kollidon 12PF and Kollidon 17PF Surfactants: Solutol HS15 and Cremophor ELP Poloxamers: Lutrol F Thickeners High molecular povidone: Kollidon 90 F Poloxamer 407: Lutrol F Solvents Low molecular weight macrogols: Lutrol E grades Propylene glycol Taste masking agents Drug stabilizers for solutions Stabilizers in injectables Stabilizers in oral and topical solutions D, L-alpha-Tocopherol as antioxidant Enhancers of bioavailability in injectables Film formers for topical aerosols Lyophilization agents Sustained-release agents in veterinary injectables Reduction of toxicity of active ingredients 116 3

5 5. Suspensions 5.1 Sedimentation inhibitors for oral and topical use Crospovidone: Kollidon CL-M Povidone: Kollidon 90 F, Kollidon 30, Kollidon Poloxamers: Lutrol F 68, Lutrol F Surfactants: Cremophor RH 40, Cremophor EL Redispersing agents for oral and topical use Crospovidone: Kollidon CL-M Povidone: Kollidon 90 F, Kollidon Sedimentation inhibitors and redispersing agents for injectables Low molecular povidone: Kollidon 12PF or Kollidon 17PF Surfactant: Solutol HS Crystallization inhibitors, solubilizers Solvent: 1,2-Propylene glycol Surfactants: Cremophor RH 40, Cremophor EL Macrogols: Lutrol E300, Lutrol E Taste masking agents Crospovidone: Kollidon CL-M Poloxamers: Lutrol F Stabilizer of active ingredients in instant granules and dry syrups Semisolid dosage forms 6.1 Emulsifiers: Cremophor A grades Gel forming agents: Lutrol F Solubilizers: Cremophor RH 40, Lutrol F grades Absorption enhancers Complex formers: Kollidon 25, Kollidon 30, Kollidon CL-M Solvent: 1,2-Propylene glycol Solubilizers: Cremophor RH 40, Lutrol F Solvents Liquid macrogols: Lutrol E grades Propylene glycol Carriers for suppositories and ovulae Bioadhesives, film-forming agents for transdermal systems Povidone and copovidone Polyacrylate Diagnostic products 7.1 Enzym stabilizers List of BASF pharmaceutical excipients and their pharmacopoeial monographs Alphabetical index 159 4

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7 Foreword This book describes the wide range of applications and functions of the excipients manufactured by BASF SE for the pharmaceutical industry. The spectrum of applications is remarkably broad, as can already be seen from the list of contents. It covers many fields of application in solid dosage forms such as instant-release and controlled-release tablets, applications in liquid dosage forms as solutions, suspensions and dry syrups, as well as many functions in semisolid dosage forms. In addition to the applications given here, there are a number of minor speciality areas of lesser importance. Details and descriptions of the BASF excipients can be found in the Technical Informations for the products concerned and in the books Kollidon, Polyvinylpyrrolidone excipients for the pharmaceutical industry and Kollicoat Grades, Functional Polymers for the Pharmaceutical Industry. Both books are available on request at BASF SE. Most of the formulations given here have been taken form the Generic Drug Formulations compendium also available on request. The 3 rd edition was actualized and revised by the inclusion of new excipients such as Kollicoat IR grades, Kollidon CL-F, Kollidon CL-SF, Kollidon VA 64 Fine and Ludiflash, by the inclusion of new technologies such as melt extrusion and of several new formulations. 6

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10 1. Instant-release solid dosage forms (Tablets, granules, pellets) 1.1 Binders General notes Among the most important binders for the manufacture of tablets, granules and pellets are povidone (e.g. Kollidon 30) and copovidone (e.g. Kollidon VA 64). They can be used in practically all the usual granulation and tabletting processes: - Wet granulation - Dry granulation (roller compaction) - Melt extrusion - Direct compression Kollicoat IR would also be capable of acting as a binder in the wet granulation technology. Direct compression excipients that contain a binder, such as Ludipress grades or Ludiflash play an increasingly important role in the production of generic products. The sustained-release matrix bases Kollidon SR and Kollicoat SR 30D also demonstrate strong binding properties in tablets Binders for wet granulation Kollidon 25, Kollidon 30, Kollidon 90 F, Kollidon VA 64 The three grades of povidone, Kollidon 25, Kollidon 30 and Kollidon 90 F, as well as copovidone (Kollidon VA 64) are very suitable for wet granulation, whether the granulation of the active ingredient with a binder solution or the granulation of a mixture of the active ingredient and binder with the solvent only (usually water). The most widely used methods of wet granulation are the following: Traditional mixer granulation and drying on hurdles Mixer granulation with fluidized bed drying Fluidized bed granulation Extrusion Quantities of 2 5% of the tablet weight are required in the case of Kollidon 25, Kollidon 30 and Kollidon VA 64, but only 1 3 % in the case of Kollidon 90 F. This difference is due to the higher molecular weight of Kollidon 90 F which gives it greater binding power. The formulation for naproxen tablets in Table 1.1 is a typical example in which an active substance is granulated with a binder solution, but without a filler. 9

11 Table 1.1: Naproxen Tablets (450 mg) 1. Formulation I. Naproxen (Syntex) g II. Kollidon g Water 90.0 g III. Magnesium stearate (Merck) 2.5 g Kollidon CL 10.0 g 2. Procedure (binder solution granulation) Granulate mixture I with solution II pass through a 0.8 mm sieve, add III and press to tablets with low compression force. 3. Tablet properties Weight 511 mg Diameter 12 mm Hardness 95 N Disintegration 3 min Friability 0.3 % Dissolution, ph 7.4 (10 min) 87 % The formulation for gemfibrozil tablets is an example for solvent granulation (Table 1.2). It would be possible to replace the ethanol in this formulation with water, though the optimum quantity would have to be determined. Particularly with solvent granulation, the quantity of solvent (e.g. water) strongly influences the properties of the tablets obtained. Also, the physical properties of the binder, in particular its particle structure and size, have a significant effect on the hardness of the tablets. This is illustrated in Fig. 1.1 for aminophylline tablets, the granules for which contained the same quantity of two different binders (6 g Kollidon 30 and 6 g Kollidon VA 64), but were made with different quantities of water. Until about 30 ml of water Kollidon 30 is more sensitive to the amount of water used in granulation than Kollidon VA 64. With the latter, adequate tablet hardness is obtained with relatively small quantities of liquid. 10

12 Table 1.2: Gemfibrozil Tablets (600 mg) 1. Formulation I Gemfibrozil 600 g Corn starch 200 g Kollidon CL 20 g Aerosil 200 (Degussa) 30 g Kollidon VA g II Ethanol 96 % (or water) about 72 g III Kollidon CL 20 g Macrogol 6000, powder 10 g Talc 40 g Magnesium stearate 8 g 2. Procedure (solvent granulation) Granulate mixture I with ethanol II, dry, pass through a 0.8 mm sieve and mix with the components III. Press with high compression force (e. g. 28 kn) to tablets 3. Tablet properties Weight 950 mg Diameter 16 mm Hardness 151 N Disintegration 2 min Friability 0.7 % Dissolution, USP (paddle), 10 min 70 % 20 min 84 % Solvent granulation with Kollidon VA 64 not only has the economic advantage that it is not necessary to dissolve the binder. It is particularly suitable if the capacity of the powder to be granulated is too small for the quantity of solvent that would be necessary to dissolve the binder. 11

13 80 Hardness, N Kollidon VA64 Kollidon Amount of water, ml Aminophylline 100 g, Starch 100 g, Kollidon 6 g, Mg stearate 1.5 g Fig. 1.1: Solvent granulation: Influence of the amount of water on the hardness of aminophylline tablets Kollidon 25, Kollidon 30, Kollidon 90 F and Kollidon VA 64 can also be used to produce pellets and granules by wet granulation. The spheronization of a verapamil drug pellet formulation is described in Table 1.3 as an example. Table 1.3: Verapamil spheronized pellets (48 %) 1. Formulation I Verapamil HCI (BASF) 480 g Microcrystalline cellulose 300 g Kollidon VA g Aerosil 200 (Degussa) 25 g Talc 175 g II Water 400 g 2. Procedure Granulate the mixture (I) in a Diosna granulator with water (II) and pass the moist granules through a sieve of 1.5 mm. Pelletize in a spheronizer at a speed of rpm. Dry the pellets in a fluidized bed and pass over a 0.7 mm sieve to remove the fines. 12

14 Kollicoat IR in wet granulation The instant-release film-coating polymer Kollicoat IR (polyvinyl alcohol grafted onto polyethylene glycol, see Section 1.6.2) also can be used as an excellent binder in the wet granulation using a binder solution. This plastic polymer is very soluble in water and alcohol, does not form any peroxides during storage and gives good physical tablet properties. Particularly the plasticity of this binder is of strong interest. In Table 1.4 the comparison of Kollicoat IR with the strong binder Kollidon 90 F is shown using a very sensitive and difficult formulation of 500 mg acetaminophen in a 610 mg tablet. Kollicoat IR gave the hardest and best tablets. Kollidon 30 did not work in this formulation and also in the case of Kollidon 90 F a certain part of the tablets showed a capping effect. Due to its high plasticity Kollicoat IR gave tablets without any capping. The granules produced with Kollidon 90 F were coarser but newertheless the flowability of the granules of Kollicoat IR was better. Table 1.4: Acetaminophen tablets (500 mg) produced with Kollicoat IR or Kollidon 90F as binder 1. Formulation I. Acetaminophen crystals 500 mg Lactose monohydrate 50 mg II. Kollicoat IR or Kollidon 90F 24 mg Water q.s. III. Kollidon CL 20 mg Magnesium stearate 6 mg 2. Procedure (wet granulation) Granulate the dry mixture I with the solution II, dry, mix with III and press to tablets with high compression force (about 20 kn) on a rotary press 3. Tablet properties Kollicoat IR Kollidon 90F Weight 617 mg 603 mg Diameter 12 mm 12 mm Hardness 54 N 40 N Disintegration time 3 min 1 min Friability <0.1 % 2 % Proportion of capped 0 % 25 % tablets A further formulation example with Kollicoat IR as binder is shown in Section

15 1.1.3 Binders for dry granulation (roller compaction) Kollidon 25, Kollidon 30, Kollidon VA 64, Kollidon VA 64 Fine Kollidon 25, Kollidon 30, Kollidon VA 64 and Kollidon VA 64 Fine can also be used in compaction processes. The Kollidon VA 64 grades are particularly suitable for this application because of their higher plasticity. The quantities required are usually the same as those for wet granulation: 2 6 % weight, in the tablet. Table 1.5 shows a typical formulation with 4.7 % Kollidon 30 for this application for a high-dose vitamin C tablet with excellent physical properties in spite of the high active concentration. Table 1.5: Vitamin C Tablets (500 mg) obtained by roller compaction with Kollidon Formulation I. Ascorbic acid powder (BASF) 500 mg Kollidon mg II. Sorbitol, crystalline 50 mg Macrogol 6000, powder 37 mg Orange flavour 3 mg Cyclamate sodium 10 mg 2. Procedure Pass mixture I through a roller compactor, mix with the components II and press to tablets with low to medium compression force 3. Tablet properties Weight 640 mg Diameter 12 mm Hardness 120 N Disintegration 6 7 min Friability 0.1 % Kollidon VA 64 Fine was specially tailored for the application in roller compaction and is the material of choice in terms of particle size distribution and particle shape for this application. Due to the particle size it is able to cover a big surface area and to form numerous bridges in the tablet structure that lead to hard tablets with a reduced friability. The formulations of allopurinol granules and tablets shown in Tables 1.6 and 1.7 are typical examples for a formulation using this technique with about 3.5 % of Kollidon VA 64 Fine in the final tablets. 14

16 Table 1.6: Allopurinol granules obtained by roller compaction with Kollidon VA 64 Fine 1. Formulation Allopurinol 100 g Ludipress 50 g Kollidon VA 64 Fine 10 g Kollidon CL 6 g Magnesium stearate 1 g 2. Compaction conditions Roller compactor Gerteis Type Mini-Pactor M1114 Roll width 25 mm Compression force 2 kn/cm Gap width 3 mm Tamping/feeding ration 120 % Roll speed 2 rpm Mesh sizes 1.25 mm After the compaction process the obtained allopurinol granules of the formulation of Table 1.6 were blended for 10 minutes with the tabletting excipients Ludipress and magnesium stearate mentioned in Table 1.7 and pressed to tablets of about 100 mg of active ingredient. Table 1.7: Allopurinol tablets prepared with compacted allopurinol granules from Table Formulation Allopurinol granules obtained by roller compaction 160 mg Ludipress 120 mg Magnesium stearate 0.9 mg 2. Procedure (Direct compression) Mix the components and press with the compression force of about 16 kn on a rotary press to tablets of the following properties: 3. Tablet properties Diameter 8 mm Weight 281 mg Hardness 246 N Disintegration time 9 min Friability <0.1 % 15

17 Plasticity Binders for direct compression Kollidon VA 64, Kollidon VA 64 Fine Copovidone is widely used as a binder in direct compression. It has a higher plasticity than other binders, a low hygroscopicity, a low glass transition temperature, and it gives hard tablets, making it the best dry binder available. Fig. 1.2 shows the comparison of the plasticity of different dry binders pressed to tablets with 0.5 % of magnesium stearate. It is interesting that not only the absolute plasticity is higher in the case of copovidone but also there is almost no influence of the compression force on the plasticity. 1.0 Compress. force 25 kn 0.9 Compress. force 18 kn HPMC Microcryst. Cellulose Povidone K 30 Kollidon VA 64 Fig. 1.2: Plasticity of different dry binders mixed with 0.5% of magnesium stearate in tablets (Plasticity = plastic energy/total energy) Kollidon VA 64 grades have a more irregular particle structure than Kollidon 25 or Kollidon 30. The finer particle size of Kollidon VA 64 Fine and the structure are the principal explanations why Kollidon VA 64 grades give harder tablets in the direct compression that povidone (see Fig. 1.3) although in the binder solution granulation there is no difference. Kollidon VA 64 and Kollidon VA 64 Fine can be used as dry binders together with all fillers and practically all active ingredients. A mixture with microcrystalline cellulose has been found to be a particularly effective combination. The usual concentration of Kollidon VA 64 grades used in the direct compression of tablets is 2 8 %, though this can be increased considerably, as, unlike many other binders like povidone, its binding effect continues to increase with the concentration even beyond 5 %, which is reflected in the tablet hardness. Fig. 1.3 illustrates this effect in ascorbic acid tablets. 16

18 Hardness, N % % 10 % % 0 % 5 % 10 % 15 % 50 Kollidon VA 64 Kollidon 30 Fig. 1.3: influence of the dry binder concentration on the hardness of vitamin C tablets (40 % ascorbic acid pressed with Ludipress + Kollidon ) It is normally difficult to produce tablets with ascorbic acid by direct compression, but they can be produced much more readily using Kollidon VA 64. When this dry binder is added, the hardness of the tablets increases and the friability decreases much more than after the addition of Kollidon 30 or hypromellose which had no effect on the hardness in such formulation. For the comparison of several dry binders including Kollidon VA 64 Fine and hypromellose (HPMC) a formulation of acetylsalicylic acid tablets was used (Composition: acetylsalicylic acid 500 mg, microcrystalline celullose 200 mg, dry binder 60 mg, Kollidon CL 25 mg, magnesium stearate 3 mg). Fig. 1.4 demonstrates that the dry binding effect of Kollidon VA 64 Fine is much higher than the effect of all other binders including normal Kollidon VA 64. The hardness of the tablets produced with Kollidon VA 64 Fine was about the double in comparison with the hardness of the tablets obtained with povidone K30, hypromellose (HPMC) or hydroxpropyl cellulose (HPC). 17

19 Hardness, N hardness at 10 kn hardness at 18 kn hardness at 25 kn without Binder Kollidon VA Kollidon VA 64 Fine Povidone K HPMC 6 mpas HPC Fig. 1.4: Hardness of acetylsalicylic acid tablets (500 mg) obtained by direct compression with different dry binders The combination of Kollidon VA 64 with sucrose and microcrystalline cellulose is mentioned for vitamin C chewable tablets in the commentary to the German Standard Generic Formulations ( Standardzulassungen für Fertigarzneimittel published by Deutscher Apothekerverlag, 1988). Table 1.8 shows the recommended formulation and the properties of these chewable tablets reproduced in the laboratory with the dosages of 100 mg, 500 mg and 1000 mg of ascorbic acid. 18

20 Table 1.8: Vitamin C chewable tablets (100 mg, 500 mg, 1000 mg) 1. Formulations Ascorbic acid, powder 42.2 % Microcrystalline cellulose 28.3 % (e.g. Avicel PH101, FMC) Sucrose, powder 13.0 % Sucrose, crystalline 8.0 % Kollidon VA % Cyclamate sodium 2.4 % Macrogol 6000, powder 2.0 % Orange flavour + strawberry flavour (2+1) 1.2 % Aerosil 200 (Degussa) 0.2 % Saccharin sodium 0.1 % 2. Procedure (direct compression) Pass all components through a 0.8 mm sieve, mix and press with medium to high compression force. 3. Tablet properties Vitamin C content/tablet 100 mg 500 mg 1000 mg Weight 250 mg 1250 mg 2500 mg Diameter 8 mm 15 mm 20 mm Form biplanar biplanar biplanar Hardness 157 N >100 N >150 N Disintegration (water) 15 min >15 min 14 min Friability <-0.1 % 0.8 % 0.6 % 19

21 1.1.5 Binders for melt extrusion Kollidon VA 64, Kollidon VA 64 Fine, Kollidon 30 The most important newer technology for the application of Kolldion VA 64 or Kollidon 30 as binder and matrix former is the melt extrusion. In this technology they also can be combined with surfactants. A drug containing Kollidon VA 64 and the anti-hiv protease inhibitors lopinavir and ritonavir was the first co-formulated pharmaceutical compound to be successfully tabletted using a proprietary melt extrusion process. The melt extrusion appears to have overcome the poor solubility and negligible oral bioavailability of previous formulations of lopanavir/ritonavir. Similar results of dissolution increase were publishes with lacidipine and indomethacin melt extruded with copovidone. A typical example of an estradiol tablet was taken from the literature. Table 1.9 shows the formulations of the granules obtained by melt extrusion and the final tablets produced with these granules. Kollidon VA 64 grades have the advantage of their higher plasticity in comparison with other polymers like povidone or macrogol. Table 1.9: Estradiol tablets produced by melt extrusion 1. Formulation of the granules (melt extrusion) 17ß-Estradiol hemihydrate 10.0 % Kollidon VA % Gelucire 44/14 (Gattefossé) 40.0 % 2. Formulation of the tablets (direct compression) 17ß-Estradiol hemihydrate melt extruded granules 8.3 % Microcrystalline cellulose 45.6 % Corn starch 45.6 % Magnesium stearate 0.5 % 3. Tablet properties Content of 17ß-estradiol hemihydrate 2 mg Diameter 6 mm Dissolution of the granules see Fig. 1.5 Fig. 1.5 shows the almost 20-fold increase of the dissolution for the melt extruded 17ß-estradiol granules produced with Kollidon VA 64. The dissolution media was 0.1 N hydrochloric acid. 20

22 17ß-Estradiol dissolved, % Melt extruded granules with Kollidon VA 64 17ß-Estradiol hemihydrate alone Time, min Fig. 1.5: Dissolution of 17ß-estradiol hemihydrate granules obtained by melt extrusion with Kollidon VA 64 21

23 1.2 Disintegrants for normal tablets General notes The crospovidone grades, Kollidon CL, Kollidon CL-F, Kollidon CL-SF and Kollidon CL-M differ mainly in their particle size. One of the possible methods for the determination of the particle size distribution is the laser light diffraction measurement (e.g. in a Malvern Mastersizer, Malvern Instruments). By this method the following typical values of the volume average diameter D[4.3] were found: - Kollidon CL: µm - Kollidon CL-F: µm - Kollidon CL-SF: µm - Kollidon CL-M: 3 10 µm Kollidon CL is the usual disintegrant for normal tablets, Kollidon CL-F and Kollidon CL-SF can be used as disintegrants for special cases and the micronized type Kollidon CL-M is mainly applied as stabilizer in liquid dosage forms like suspensions, instant drink granules and dry syrups. Crospovidone is referred to as one of the super disintegrants in the literature but it is also an excellent agent for the enhancement of the drug release (see Section 1.4.3). The Kollidon CL grades can be used for all tabletting technologies like granulation, direct compression etc.. Table 1.10 gives a overview of the general properties and functions of the three Kollidon CL grades normally used as disintegrants in tablets. Table 1.10: Comparison of general properties of Kollidon CL grades used as disintegrants Product Disintegration Mouthfeel Smooth tablet Adsorption Drug power surface of granulation dissolution liquid Kollidon CL ++ +/ ++ Kollidon CL-F + + +/ + + Kollidon CL-SF / 22

24 1.2.2 Standard disintegrant Kollidon CL Kollidon CL is used as the standard disintegrant for all kind of different tablet formulations. Since many years the pharmaceutical industries know quite well the performance of the material. Main reasons for taking this disintegrant is the strongest disintegration power with benefits especially in large tablets. It has advantages compared to other disintegrants which are based on a different chemistry due to disintegration and dissolution speed. The particle size of Kollidon CL must be regarded as a compromise: although even coarser particles provide a slightly better disintegration effect than Kollidon CL, the latter probably gives tablets whose surface finish is less affected by humidity than tablets made with a coarser crospovidone which does not contain the fine fraction that makes up the major portion of Kollidon CL. But it must be stated that the differences of few minutes of the disintegration time of a tablet normally have no significant influence on the dissolution of the active ingredient. In the wet granulation process, Kollidon CL can be incorporated after granulation, or in the intragranular use, as its swelling action is completely reversible. In difficult cases, it is recommended to add some of the Kollidon CL before granulation, and some after. This has been done with the formulation of a gemfibrozil tablet shown in Table 1.2, as the active substance has a relatively low melting point and can therefore sinter together on compression. If part of the Kollidon CL were not added before granulation, the disintegration time of the resulting tablets would be much longer. Obviously, Kollidon CL is also very suitable for use in formulations for direct compression. Typical examples are those for a piroxicam tablet in Table 1.11 and an acetylsalicylic acid tablet in Fig

25 Table 1.11: Piroxicam tablets (20 mg) 1. Formulations Piroxicam Corn starch Ludipress Kollidon CL Macrogol 6000, powder Aerosil 200 (Degussa) 20 g 150 g 50 g 8 g 10 g 1 2 g 2. Procedure (direct compression) Mix all components, pass through a 0.8 mm sieve and press with low to medium compression force. 3. Tablet properties Weight 238 mg Diameter 8 mm Form biplanar Hardness 66 N Disintegration (water) 57 sec Friability 0.1 % The rapid disintegration of a tablet is by no means a guarantee that the active substance is dissolved and made bioavailable quickly. Thus, the drug dissolution is a much more important criterion than its disintegration time. Kollidon CL is often very effective in this respect, as can be seen from Fig. 1.6 which contains data for acetylsalicylic acid tablets made by direct compression. Although both tablets, with and without Kollidon CL, disintegrate within about 4 minutes, the difference in drug release remain considerable even after 60 minutes. Table 1.12 and also Fig. 1.7 in the next Section show the comparison of disintegration and dissolution of analgesic tablets caused by Kollidon CL grades and other disintegrants. 24

26 Dissolved drug, % + 3 % Kollidon CL Without Kollidon CL Disintegration time of both formulations: max. 4 min Time, min Fig. 1.6: Influence of Kollidon CL on the dissolution of acetylsalicylic acid tablets (Acetylsalicylic acid 400 mg, Ludipress 99 mg, stearic acid 1 mg) The direct compression agent Ludipress contains 3.5% Kollidon CL. Therefore usually it also acts as a disintegrant. The disintegrant effect is adequate, if the content of Ludipress in the tablet is high enough. However, if tablets made with Ludipress are found to disintegrate too slowly, it is recommended to add Kollidon CL to the formulation. Such a formulation for acetylsalicylic acid tablets is given in Fig

27 1.2.3 Special disintegrants Kollidon CL-F, Kollidon CL-SF Kollidon CL-F has a strong disintegration power although the particles are finer compared with Kollidon CL. Tablets containing Kollidon CL-F do not tend to form rough surfaces after storage under humid conditions. Therefore it is a perfect alternative to Kollidon CL when formulators are looking for a disintegrant with short disintegration time and fast dissolution in combination with a smooth tablet surface. With Kollidon CL rough surfaced tablets might occur with very hygroscopic formulations packed in a multidose packaging. This sensitivity increases with a decreased size of the tablet. As a consequence Kollidon CL-F (or Kollidon CL-SF) should be taken for the development of small tablets. Furthermore Kollidon CL-F and even more Kollidon CL-SF are able to adsorb large amounts of liquid (see Table 1.10). This behaviour can be beneficial when large amounts of granulation liquid have to be used for wet granulation (e.g. for dissolving the active ingredient in the granulation solvent). Table 1.12 and Fig. 1.7 show the comparison of the three Kollidon CL grades normally used as disintegrants with other substances like croscarmellose or carboxymethyl starch in two different analgesic tablets. In both formulations the disintegration and the drug dissolution is faster using Kollidon CL grades. Table 1.12: Comparison of disintegrants in analgesic tablets 1. Composition I. Acetaminophen cryst. 250 mg Acetylsalicylic acid cryst. 250 mg Caffeine cryst. 50 mg II. Kollidon 90 F (dissolved in 2-propanol) 17 mg III. Magnesium stearate 5 mg Disintegrant 27 mg 2. Procedure (wet granulation) Granulate Mixture I with Solution II, sieve through a 1000 µm sieve, dry and mix 10 min with III and press on a rotary tablet press with a high compression force of 18 kn. 3. Disintegration times of the tablets in synthetic gastric juice Disintegrant Min None > 60 Kollidon CL 9 Kollidon CL-F 11 Kollidon CL-SF 9 Croscarmellose 23 Carboxymethyl starch 34 26

28 Apart from the enhancement of the tablet disintegration it is even more important that the dissolution of the active ingredient is increased as well to achieve a fast resorption of the drug. Fig. 1.7 shows an example of dissolution data of an acetaminophen tablet with 2.7 % of different disintegrants including three Kollidon CL grades. In some formulations there is no significant difference of the dissolution between the disintegrants, in other formulations the difference is strong. But allways the increase of the dissolution in comparison with the tablets without disintegrant is enormous. 100 Acetaminophen dissolved, % Kollidon CL Kollidon CL-F Kollidon CL-SF Croscarmellose Caroxymethyl starch Time, min Fig. 1.7: Dissolution of an acetaminophen tablet (2.7 % disintegrant) 27

29 1.3 Disintegrant for fast disintegrating buccal tablets Kollidon CL-SF Kollidon CL-SF is the finest crospovidone grade for disintegration and it has a good disintegration power and less surface defects of the tablets after humid storage. This grade is perfect for fast disintegrating tablets (e.g. Flash tabs ) since it gives a very smooth cream-like mouth feel superior to the other Kollidon CL types. For this kind of tablets first of all of analgesics a superdisintegrant like crospovidone is used to obtain a disintegration within much less than one minute. A typical example mentioned in the literature is ibuprofen. Table 1.13 illustrates the practical use of Kollidon CL-SF in a formulation of fast disintegrating buccal tablets of loperamide. The disintegration time of these tablets is 27 sec. Table 1.13: Fast disintegrating buccal loperamide tablets with Kollidon CL-SF 1. Formulation I. Loperamide-HCl (Select Chemie) 2.0 mg Mannitol powder (Roquette) 85.5 mg Kollidon CL-SF 4.0 mg II. Kollicoat IR 3.0 mg Water 27.0 mg III. Kollidon CL-SF 3.0 mg Chocolate flavour (Symrise) 1.5 mg Sodium stearyl fumarate (JRS Pharma) 1.0 mg 2. Procedure (wet granulation) Granulate mixture I with binder solution II in a fluidized bed granulator (inlet air temperature C, outlet air temperature 30 C, atomizing pressure 0.5 bar), mix with the components III, pass through a 0.8 mm sieve, blend and press on a rotary press with low compression force (about 4 kn). 3. Tablet properties Weight 100 mg Diameter and form 7 mm, concave Hardness 27 N Disintegration in water 27 sec Friability less than 0.2 % Dissolution (0.01 N HCl/100 rpm) 84 % after 5 min, 94 % after 10 min Content uniformity corresponds to Ph.Eur. 28

30 Due to its interesting properties Kollidon CL-SF also forms a part of a new direct compression agent (Ludiflash ) developed as direct compression agent for the production of fast disintegrating buccal tablets (see Section 1.5.4). It is a preparation of mannitol, Kollidon CL-SF and polyvinyl acetate. Furthermore Kollidon CL-SF shows the strongest ability of all Kollidon CL grades to adsorb water or ethanol. 29

31 1.4 Enhancers of drug release General notes One problem with many of the active ingredients used today is their poor solubility in water and their limited bioavailability in solid dosage forms. If the usual concentration of a tablet disintegrant like crospovidone does not solve the problem an other method must be found. The simplest means of improving the bioavailability of a drug is to enhance its dissolution by adding complex formers or solubilizing agents, such as povidone, crospovidone, poloxamers or surfactants. In many cases it may be sufficient to produce a physical mixture or a trituration of the active ingredient with the solubilizer or complex former Povidone Soluble Kollidon grades Povidone, e.g. Kollidon 25 or Kollidon 30 has no disintegrant effect whatsoever, but it can be used to improve the dissolution of many drugs by forming a soluble complex with them. To this end, as with Kollidon CL, it is necessary to prepare an intimate mixture of povidone and drug by comilling, or mixing (or coprecipitation or coextrusion) that contains an excess of Kollidon 25 or Kollidon 30. Fig. 1.8 shows a typical example of a physical mixture with indomethacin in the ratio 1+2. After 30 min the dissolution of the active ingredient was about 10 times enhanced by the presence of Kollidon 30. Dissolved indomethacin, % Kollidon CL-M Kollidon Indomethacin alone Time, min Fig. 1.8: Enhancement of the dissolution of indomethcin by mixing with Kollidon 30 or Kollidon CL-M in the ratio

32 1.4.3 Crospovidone as enhancer of drug release Kollidon CL grades The rapid disintegration of a tablet is by no means a guarantee that the active substance is released and made bioavailable quickly. Thus, the drug release rate of a tablet is a much more important criterion than its disintegration time. Kollidon CL is often very effective in this respect, as can be seen from Fig. 1.6 (Section 1.2.2) which contains data for acetylsalicylic acid tablets made by direct compression. But in difficult cases of insoluble active ingredients where drug release still proves inadequate, higher concentrations of crospovidone can be used to solubilize the active ingredient by complex formation as it is well known in the case of povidone. Then, the active substance should be mixed or comilled (or perhaps coevaporated) with one of the Kollidon CL grades before addition to the other ingredients. The complex formed between the active ingredient and crospovidone in these intimate mixtures increases the dissolution and bioavailability of the drug. Such preparations generally require an excess of crospovidone, typically 2 to 6 parts per 1 part of active ingredient. With active substances that are used in low dosages, such as hormone derivatives, this presents no problems. A typical enhancement of the drug dissolution is shown in Fig. 1.8 in the case of the example of a physical mixture of indomethacin and Kollidon CL-M (or Kollidon 30) in the ratio 1+2. A very high increase of the drug release was observed within the tested period of 2 hours. A typical example of this application from the literature is a tablet formulation of medroxyprogesterone. Fig. 1.9 shows the influence of a trituration of this active ingredient with crospovidone on the dissolution of the tablet. 31

33 Drug, dissolved, mg/ml Medroxyprogesterone acetate + crospovidone (1 + 6) Medroxyprogesterone acetate alone Time, min Fig. 1.9: Dissolution of medroxyprogesterone acetate from tablets made from a trituration with Kollidon CL, compared with tablets without crospovidone Poloxamers as enhancers of drug release Lutrol F 68, Lutrol F 127, Lµtrol micro 68, Lµtrol micro 127 Like Kollidon 25 and Kollidon 30 the poloxamers 188 and 407 in the normal particle size (Lutrol F 68, Lutrol F 127) or in the milled form (Lµtrol micro 68, Lµtrol micro 127) can be used in tablets and capsules to improve the drug release. Fig shows the influence of Lutrol F 68 on the dissolution of digitoxin in a physical mixture 1+9. The dissolution of the active ingredient could be doubled by this combination. Preparing a coprecipitate with the same ratio the dissolution of digitoxin reached until more than 11 µg/ml after 120 min. 32

34 Dissolved drug, mg/ml 6 4 Digitoxin + Poloxamer 188 (1+9) Digitoxin alone Time, min Fig. 1.10: Influence of Lutrol F 68 on the dissolution of digitoxin Because of the large particle size of the standard grades Lutrol F 68 and Lutrol F 127 it is recommended to use a preparation of the poloxamer with the active ingredient obtained by comilling, coextrusion or coprecipitation before tabletting. It must be noted that the comilling procedure is only possible if the mill is cooled, as the Lutrol F grades have a melting point in the C range. If only a physical mixture of the active ingredient with Lutrol F will be applied (e.g. for the direct compression technology), it would be preferable to use the milled products Lµtrol micro 68 and Lµtrol micro 127 instead of the standard grades Solubilizer as enhancer of drug release Cremophor RH 40 In recent years, Cremophor RH 40, the nonionic solubilizer macrogol glycerol hydroxystearate 40, has increasingly been used in solid drug forms to improve drug release. Unlike most other solubilizers, this product is almost odourles and tasteless in water, which is an advantage in this application. In wet granulation, a small amount (usually less than 1% of the weight of the finished tablets) of Cremophor RH 40 is dissolved in the granulating fluid or the binder solution, before starting the granulation. This is of particular interest in the case of lipophilic or strongly hydrophobic drugs that can be solubilized as micelles. 33

35 1.5 Direct compression agents General notes The direct compression of tablets is of increasing interest particularly for generic preparations. Since the majority of the active ingredients don t have the needed physical properties for the direct compression (flowability, particle size and particle structure) a direct compression agent can solve this problem. In the product range of BASF excipients there are direct compression agents for different types of tablets as shown in Table All these products act as flowability agent, filler, binder and enhancer of the content uniformity of tablets. Furthermore the standard grade Ludipress and also Ludiflash contain crospovidone as disintegrant. Table 1.14: Direct compression agents of BASF Product Ludipress Ludipress LCE Ludiflash Type of tablet Normal tablets Lozenges, chewable tablets, effervescent tablets sustained-release tablets Fast disintegrating buccal tablets Direct compression of normal tablets Ludipress Ludipress is a direct compression agent based on lactose monohydrate as filler and it contains 3.5 % of Kollidon 30 as a binder and 3.5 % of Kollidon CL as disintegrant. Fig shows the comparison of Ludipress and a physical mixture of the same components in identical proportions like in Ludipress. This Figure gives one of the important justifications of the commercialization of Ludipress since the tablet hardness is much higher in comparison to the physical mixture. Ludipress is suited above all for normal tablets with a low to medium dosage of active ingredients. The irregular structure of the particles of the Ludipress grades illustrated in Fig (Section 1.5.3) explains the good content uniformity of tablets even with very low dosages of the active ingredient. 34

36 Hardness Ludipress Phys. mixture (like Ludipress) Compression force, kn Fig. 1.11: Hardness of placebo tablets manufactured with Ludipress or with an iidentical physical mixture like Ludipress Table 1.15 shows a typical direct compression formulation of aminophyllline tablets as a example of the many available guide formulations containing Ludipress. Table 1.15: Aminophylline tablets (100 mg) 1. Formulation Aminophylline powder (BASF) Ludipress Magnesium stearate Aerosil 200 (Degussa) 100 g 150 g 2 g 2 g 2. Procedure (direct compression) Mix all components, sieve and press on a rotary press to tablets with low compression force. 3. Tablet properties Weight 254 mg Diameter 8 mm Hardness 97 N Disintegration 10 min Friability 0.2 % Dissolution 10 min: 87 % 15 min: 100 % 35

37 1.5.3 Direct compression of lozenges, chewable, effervescent and sustained-release tablets Ludipress LCE Ludipress LCE is a direct compression agent based on 96.5 % lactose monohydrate and 3.5 % of Kollidon 30 as binder. It does not contain any disintegrant and is therefore suitable for all tablets of slow disintegration (lozenges, chewable and sustained-release tablets) or which contains an other system of disintegration like effervescent tablets. Beside of the function as filler, flowability agent and binder Ludipress LCE can be suitable as pore former in sustained-release matrix tablets of insoluble active ingredients to adjust its release. Both Ludipress grades have a particle structure (see Fig. 1.12) that gives them excellent flow properties, and their concentration in tablets is often fairly high, they are also effective flow improvers. Fig. 1.12: Particle structure of the Ludipress grades Table 1.16 shows a typical direct compression formulation of acetylsalicylic acid + vitamin C effervescent tablets as an example of the many available guide formulations containing Ludipress LCE. 36

38 Table 1.16: Acetylsalicylic acid + vitamin C effervescent tablets (400 mg mg) 1. Formulation Acetylsalicylic acid (Synopharm) Ascorbic acid, crystalline (BASF) Ludipress LCE Citric acid, crystalline Sodium bicarbonate Macrogol 4000, powder 400 g 250 g 600 g 300 g 600 g 90 g 2. Procedure (direct compression) Pass all components through a 0.8 mm sieve, mix and press with high compression force. 3. Tablet properties Weight 2251 mg Diameter 20 mm Hardness 145 N Disintegration 1 min 35 sec Friability 0.66 % Colour white Direct compression of fast-disintegrating buccal tablets Ludiflash Ludiflash is a formulation of about 90 % D-mannitol, 5 % Kollidon CL-SF and about 5 % polyvinyl acetate obtained by granulation with Kollicoat SR 30D. It is suitable for direct compression manufacturing of fast disintegrating tablets particularly for buccal administration having the functions of filler, disintegrant, flowability agent and binder. But it could also be used for such fast disintegrating tablets produced by wet granulation. When placebo tablets of Ludiflash were produced using different compression forces a linear influence of the compression force on tablet hardness and disintegration could be demonstrated (see Fig. 1.13). 37

39 Hardness, N Hardness Disintegration Disintegration times, s Compression force, kn 0 Fig. 1.13: Influence of compression force on the hardness and disintegration of Ludiflash placebo tablets If the disintegration is not fast enough because the amount of Ludiflash in the formulation must be small it would be recommended to add an additional amount of Kollidon CL-SF. Detailed test revealed magnesium stearate and sodium stearyl fumarate to be appropriate lubricants for fast disintegration buccal tablets based on Ludiflash. 38

40 Table 1.17 shows a typical formulation of fast-disintegrating famotidine tablets having a disintegration time of 27 sec and a dissolution of almost 100 % after 3 min. Table 1.17: Famotidine fast-disintegrating buccal tablets (20 mg) 1. Formulation Famotidine (various sources) Ludiflash Aerosil 200 (Degussa) L-Menthol Aspartame Sodium stearyl fumarate 20 g 267 g 3 g 0.9 g 4.5 g 4.5 g 2. Procedure (direct compression) Mix all components, pass through a 0.8 mm sieve and press with a compression force of about 10 kn and a rotation speed of 40 rpm. 3. Tablet properties Weight 300 mg Diameter 10 mm Hardness 51 N Disintegration (ph 7.2) 27 sec Friability < 0.2 % Dissolution (5 min) about 99 % 39

41 1.6 Instant-release and protective coatings of tablets and capsules General notes Instant-release coatings can be a subcoating (see Section 1.6.7), a final film-coating or a traditional sugar coating of tablets or capsules. Final instantrelease coatings usually are applied to tablets or capsules with one or several of the purposes mentioned in Table Table 1.18: Important purposes of final instant-release coatings 1. Colouring - Increase the patient compliance - Identification and distinction of different types of tablets. 2. Protection of the active ingredient - Against oxidation or hydrolysis - Reduction of chemical interactions between active ingredients (e.g. antibiotics, vitamin combinations). 3. Masking the smell and taste of the active ingredient In the product range of BASF excipients there are four different film-coating substances or preparations suitable for instant-release film-coatings (Table 1.19). Most of they are based on the grafted copolymer Kollicoat IR. Table 1.19: Polymers or preparations for instant-release coatings in the BASF product range Product Type Main function/application Kollicoat IR Polymer Coloured coatings, protective coatings Kollicoat IR White Ready to mix White coatings, protective preparation coatings Kollicoat Protect Polymer mixture Protection, white or coloured coatings, taste masking Kollidon VA 64 Polymer Coloured coatings, protection (combination with sugar or HPMC) 40

42 1.6.2 Instant-release film-coating with Kollicoat IR Kollicoat IR powder comprises polyethylene glycol and polyvinyl alcohol bound in the ratio of 25:75. A polyethylene glycol chain forms a base onto which side chains of polyvinyl alcohol are grafted. The mean molecular weight is approximately 45,000. It can be considered as the ideal film former for instant-release film-coatings, since it is very plastic, very soluble in water, has no significant viscosity even in a concentration of 20 % and very low tackiness. Therefore high concentrated spray solutions can be applied and no plasticizer is needed. Smooth tablet coatings are obtained and nether polishing nor curing is needed. Fig shows the viscosity of 20 % solutions in water of Kollicoat IR and two hypromellose types used for instant-release film-coating. The viscosity of Kollicoat IR solution is much lower than the usual limit of 250 mpa.s to pass well the nozzle of about 0.8 mm. Viscosity, mpa.s Usual limit of the nozzle 0 Kollicoat IR HPMC, type 3 mpa.s HPMC, type 6 mpa.s Fig.1.14: Viscosity of Kollicoat IR and hypromellose (20 % in water) The manufacture of a spray suspension of Kollicoat IR for coating tablets and capsules is straightforward; it is also quicker than with most other filmforming agents. The suspension can be prepared using a number of methods; the recommended method is described below: Suspend the pigments and talcum in part of the water and homogenize until fine and lump-free. Dissolve the Kollicoat IR in the rest of the water. Add the homogenized pigment suspension to the Kollicoat IR solution. Pass the suspension through a sieve (e.g. 200 µm) in order to remove any pigment that may have agglomerated and that would block the spray nozzle. Frequently, a simpler method is also possible: suspend the pigments in the total amount of water, homogenize and then stir in the Kollicoat IR, stirring for 5 min until dissolved. Generally, the stirring speed should not be too high in order to prevent or minimize foaming. 41

43 Table 1.20 shows a typical film-coating formulation of Kollicoat IR for tablets or capsules. The viscosity of this spray suspension is below 200 mpa.s. Table 1.20: Instant-release film-coating formulation with Kollicoat IR for 5 kg tablets (weight 330 mg, diameter 9 mm) Weight [g] Proportion [%] 1. Formulation Polymer solution: Kollicoat IR Water Pigment suspension: Talc Titanium dioxide Sicovit Iron oxide red Water Procedure Stirr the talc and the pigments vigorously into the water, homogenize the obtained suspension in a corundum disk mill and stirr it into the polymer solution. 3. Coating conditions (Accela cota 24, Manesty) Inlet air temperature 60 C Outlet air temperature 40 C Cores temperature 35 C Air flow 180 m 3 /h Spray pressure 3 bar Spray rate 30 g/min Spraying time 20 min Final drying 4 min, 60 C Quantity applied 3 mg polymer/cm 2 The tablets of propranolol or caffeine coated with the formulation given in Table 1.20 had got a smooth and brillant surface without any polishing. All other physical properties like hardness, friability, disintegration and dissolution were not changed in a significant manner by the coating and after the storage at different conditions. In the pharmaceutical industry today the question of production cost, including that of coatings, is constantly being raised. In the case of the pure material costs the difference between coating with Kollicoat IR grades and hypromellose is so small that it can be practically neglected for comparative purposes. However, production costs are a different matter. 42

44 With Kollicoat IR, the production of the polymer solution is simpler, and hence a little cheaper, than is the case with hypromellose; however, the decisive cost factor is the film-coating process and this is practically entirely dependent on the solid concentration of the spray suspension. In the case of Kollicoat IR, this concentration is about 20 % and hence substantially higher than in the case of hypromellose (about 12 %). This means that the spray time, and hence the cost, can be considerably reduced. In addition, the temperatures that can be achieved with cores comprising the Kollicoat IR grades are substantially higher than with hypromellose. In order to demonstrate this, extensive comparison studies were done in an Accela-Cota 24 (Manesty) to develop Process-Parameter-Charts. The influence of product temperature and processing time on the aspect of the coated tablets and the processing behaviour were detemined. Four groups of results were classified in these studies: - Class 1 (red area): The film-coating process is not possible with the chosen settings. Cores stick to the drum or are overwetted. - Class 2 (orange area): The film-coating process is principly possible, but the surface of the coated tablets is not acceptable. - Class 3 (light green area): The film-coating process is possible and the surface of the coated tablets is acceptable. - Class 4 (dark green area): The film-coating process is possible and the surface of the coated tablets is optimal. The Process-Parameter-Charts of Kollicoat IR and HPMC (3 mpa.s) shown in Fig.1.15 and Fig demonstrate clearly that a very robust process with short process times (about 50 min) can be achieved with Kollicoat IR. Since in the case of HPMC (3 mpa.s) the green areas are much more limited the minimal process time is much longer (at least about 100 min) and the transfer from a pilot to production scale is not so easy. In the case of HPMC (6 mpa.s) the process time is even longer than for HPMC (3 mpa.s). 43

45 Film-coating impossible, sticking of the cores Film-coating possible, but surface not acceptable Good film-coating process, surface acceptable Optimal film-coating process, best surface quality Fig. 1.15: Influence of process time and temperature on the film-coating with a Kollicoat IR formulation (Process-Parameter-Chart) Film-coating impossible, sticking of the cores Film-coating possible, but surface not acceptable Good film-coating process, surface acceptable Optimal film-coating process, best surface quality Fig. 1.16: Influence of process time and temperature on the film-coating with a HPMC (3 mpa.s) formulation (Process-Parameter-Chart) To test the scale-up of Kollicoat IR coatings a formulation similar to the red film-coating formulation described in Table 1.20 was produced on propranolol- HCl cores in various batch sizes from 5 kg to 250 kg of cores. It was found that the most important parameter to be considered for the scale-up is the relative spray rate. If a relative spray rate of 2.8 g/min was applied for 1 kg of cores, no significant differences of the coated tablets could be observed in this study. 44

46 1.6.3 Instant-release film-coating with Kollicoat IR White Kollicoat IR White is a ready-made mixture based on film-forming agent Kollicoat IR and is for immediate use (Composition: 61 % Kollicoat IR, 7 % Kollidon VA 64, 14 % titanium dioxide, 16 % kaolin, 2 % sodium lauryl sulphate). It is mainly intended for use in white tablets; however, other pigments can be added for colour if required. It has all the advantages of film former Kollicoat IR, e.g. rapid dissolution in water, a high degree of adhesion also on lipophilic surfaces, its enormous plasticity and its low viscosity in water. With Kollicoat IR White, a white, readily soluble coating is obtained. It can be used to mask taste, to facilitate swallowing tablets or to improve the stability of the active ingredient by decreasing contact with oxygen and moisture. Due to the very high flexibility of Kollicoat IR, Kollicoat IR White requires no additional plasticizer. In addition, the flexibility prevents the coating from cracking during storage, especially if the relative humidity varies. Even if the cores contain a swelling disintegrant such as crospovidone (Kollidon CL grades), the coating retains its strength during storage also if the storage conditions may not be ideal. The manufacture of a spray suspension of Kollicoat IR White for film-coating tablets and capsules is both easy and quick. The following method is recommended: Stir the required amount of water well. The stirring speed must be such that little or, better, no foam is produced. Add Kollicoat IR White slowly but continuously. Continue stirring for a further minutes; the white spraying suspension is then ready for use (see Fig 1.17). 45

47 Fig. 1.17: The fi gures Dispersion clearly of illustrate Kollicoat the simple IR White redispersion in water: of Kollicoat IR White. 1 Slightly stirred water using a magnetic stirrer prior to addition. 2 Start of addition of Kollicoat IR White. 3 During the addition of Kollicoat IR White. 4 Final homogeneous suspension. To obtain coloured coatings, water-soluble colorants or ready-made colour mixes, e.g. Sepispers Dry (Seppic), can be added directly. However, colour lakes or iron oxide pigments can also be used. They must, however, be separately dispersed in water beforehand and then homogenized before being added to the Kollicoat IR White suspension. Due to the low viscosity of aqueous Kollicoat IR White suspensions (25 % in water: about 150 mpa.s), a much higher concentration can be used than for other commercially available ready-made film-coating mixtures. This reduces the spraying time considerably and hence the overall processing costs. 46

48 Spray suspensions containing % of solids can be prepared with ease at room temperature as their viscosity is always below the critical limit of 250 mpa.s. Like in the case of Kollicoat IR a very robust process with short process times can be achieved with Kollicoat IR White. For the white film-coating of cores usually 20 % of Kollicoat IR White is suspended in water and stirred for further 15 minutes. For the coating of 6 kg of acetylsalicilic acid cores the machine settings of the Accela Cota 24" (Manesty) are summarized in Table 1.21 as a typical example. Although the inlet air temperature was relatively low at 60 C and the spraying pressure was only 2 bar, the entire spraying process took only 35 minutes. Table 1.21: Machine settings for the white film-coating of acetylsalicylic acid cores with Kollicoat IR White (Accela Cota 24") Parameter Setting Batch size 6 kg Inlet air temperature 60 C Outlet air temperature 36 C Core temperature 35 C Inlet flow rate 210 m 3 /h Outlet air flow rate 410 m 3 /h Spray pressure 2 bar No. nozzles 1 Spray rate 30 g/min Spraying time, total 35 min Subsequent drying 4 min/60 C Amount applied 5 mg solid/cm 2 The physical properties of the acetylsalicylic acid tablets were not changed significantly by the coating process. Only a slight increase of the tablet hardness was observed without any influence on the disintegration or dissolution. For the coloured film-coating of cores with Kollicoat IR White a typical formulation of the spray suspension and the machine settings are given in Table 1.22 for the scale of 250 kg of cores. This particular production run is somewhat more complex than for a simple white suspension as the insoluble indigotin-aluminium colour lake first has to be suspended and homogenized (e.g. using a high-speed mixer) before being added to the Kollicoat IR White suspension. 47

49 Table 1.22: Blue instant-release film-coating with Kollicoat IR White for 250 kg tablets (weight 250 mg, diameter 9 mm) Weight [kg] Proportion [%] 1. Formulation Polymer suspension: Kollicoat IR White Water Colour lake suspension: Indigotin colour lake E Water Procedure Stirr the colour lake vigorously into the water, homogenize the obtained suspension in a corundum disk mill and stirr it into the polymer suspension. 3. Coating conditions (Driacoater 900, Driam) Inlet air temperature 70 C Outlet air temperature 45 C Cores temperature 47 C Air flow 4600 m 3 /h Spray pressure 4 bar No. nozzles 6 Spray rate 700 g/min Spraying time 60 min Final drying 5 min, 60 C Quantity applied 3 % solids Protective film-coating with Kollicoat Protect Kollicoat Protect is a mixture of the film-forming polymers Kollicoat IR and polyvinyl alcohol in the ratio 6:4. It is designed for white and coloured tablet and capsule film-coatings. Due to its very low permeability with respect to oxygen and water, its primary application is as a protective film against oxidation and hydrolysis of the active ingredient. In addition, it can be used to mask taste, to facilitate the swallowing of tablets, to improve their appearance or as subcoating. It possesses all the advantages of Kollicoat IR, e.g. rapid dissolution in water, a high degree of adhesion, also on lipophilic surfaces, enormous flexibility and low viscosity in water (20 % in water: about 230 mpa.s). 48

50 Kollicoat Protect allows smooth and rapidly dissolving coatings to be produced. Due to its high degree of flexibility, coating formulations using Kollicoat Protect do not require the addition of a plasticizer. In addition, the flexibility prevents the coating from cracking during storage, especially if the relative humidity varies. Even if the cores contain a swelling disintegrant such as crospovidone (Kollidon CL grades), the coating retains its strength during storage also if the storage conditions may not be ideal. The manufacture of a polymer solution of Kollicoat Protect for film-coating tablets and capsules is both straightforward and quick. However, at certain stirring speeds foam may form. The formation of foam can be best prevented or at least reduced by adding 0.1 % of a 30 % simethicon emulsion or 0.75 % Labrasol (Gattefossé). Normally, one of the following two methods can be used: A) Spray solution containing a water-soluble colorant: Stir Kollicoat Protect and the soluble colorant into the required amount of water. Set the stirring speed so that as little foam as possible is generated. Continue stirring for a further 30 min. If necessary, add an anti-foaming agent beforehand. B) Spray suspension with white and/or coloured pigment or colour lake: Stir Kollicoat Protect into the required amount of water to obtain the polymer solution. Set the stirring speed so that as little foam as possible is generated. Continue to stir for a further 30 min. To prepare the pigment suspension, stir the insoluble components, e.g. talcum powder, titanium dioxide, iron oxide or colour lake into the required amount of water and homogenize in a high-speed stirrer or corundum disk mill. Stir the pigment suspension into the polymer solution to make the spray suspension. Stir continuously during the entire spraying process. A typical example of this method is demonstrated in Table The concentration of solids in the spray suspension usually lies in the range of %. The Process-Parameter-Charts of formulations of Kollicoat Protect and of polyvinyl alcohol shown in Fig.1.18 and Fig demonstrate clearly the strong advantages of the polmer combination Kollicoat Protect against the polyvinyl alcohol alone. A very robust process with short process times (about 90 min) can be achieved with the Kollicoat Protect formulation. Since in the case of the polyvinyl alcohol formulation the green areas are strongly limited the minimal process time is very much longer, the inlet-air temperature much higher and the transfer from a pilot to production scale is more difficult. 49

51 Film-coating impossible, sticking of the cores Film-coating possible, but surface not acceptable Good film-coating process, surface acceptable Optimal film-coating process, best surface quality Fig. 1.18: Influence of process time and temperature on the film-coating with a Kollicoat Protect formulation (Process-Parameter-Chart) Film-coating impossible, sticking of the cores Film-coating possible, but surface not acceptable Good film-coating process, surface acceptable Optimal film-coating process, best surface quality Fig. 1.19: Influence of process time and temperature on the film-coating with a polyvinyl alcohol formulation (Process-Parameter-Chart) For a typical formulation acetylsalicylic acid (100 mg) was selected as active ingredient for this particular application because of its high sensitivity to hydrolysis. In this way, the protective effect of Kollicoat Protect can best be shown. The 20 % suspension was prepared as described in general method B. The composition and the machine settings is shown in Table The formulation was designed for the coating of 6 kg of cores. 50

52 Table 1.23: Protective white film-coating with Kollicoat Protect for 6 kg of acetylsalicylic acid tablets (weight 300 mg, diameter 9 mm) Weight [g] Proportion [%] 1. Formulation (spray suspension) Kollicoat Protect Talcum Titanium dioxide Water Total Procedure (Method B) Stirr the talcum and titanium dioxide into a part of the water, homogenize the obtained pigment suspension in a corundum disk mill and stirr it into the polymer solution prepared with the rest of water. 3. Coating conditions (Accela Cota 24, Manesty) Inlet air temperature 60 C Outlet air temperature 36 C Cores temperature 35 C Inlet air flow 210 m 3 /h Outlet air flow 410 m 3 /h Spray pressure 2 bar No. nozzles 1 Spray rate 30 g/min Spraying time 35 min Final drying 4 min, 60 C Quantity applied 5 mg solids/cm 2 The coated acetylsalicylic acid tablets obtained had a white, glossy coating that covered the engravings on the tablet surface excellently. The physical properties of acetylsalicylic acid tablets were hardly affected by the protective coating; however, there was an small increase in hardness. The release curve is also practically identical to that of identical cores coated with Kollicoat IR. Hydrolysis of acetylsalicylic acid in the tablets coated with Kollicoat Protect was investigated over a period of 6 months under various storage conditions (25 C/60 % and 30 C/70 % relative humidity). In the case of the Kollicoat Protect coating, a significant smaller amount of free salicylic acid was determined than with a coating of Kollicoat IR White or without any coating. To obtain coloured film-coatings with Kollicoat Protect the same formulation as given in Table 1.23 could be used adding an iron oxide or a colour lake to the pigment suspension. 51

53 1.6.5 Instant-release film-coating with Kollidon VA 64 Kollidon VA 64 is used in water-soluble tablet coatings to improve stability or organoleptic properties, particularly in conjunction with other film-forming agents. A typical example is the combination with hypromellose (HPMC), in which the use of Kollidon VA 64 saves not only material costs but also processing costs, as it reduces the viscosity of the spray suspension. This allows the use of a higher concentration, which saves time. The effect of reducing the viscosity is shown in Fig Kollidon VA 64 can also be used together with other film-forming agents such as polyvinyl alcohol, hydroxypropyl cellulose (HPC), ethyl cellulose or sucrose in the manufacture of soluble tablet coatings. Viscosity, mpa s Hypromellose alone Hypromellose + Kollidon VA 64 (4+6) Limit (Accela Cota ) Polymer concentration in water, % Fig. 1.20: Viscosity of hypromellose (+ Kollidon VA 64) coating solutions The combination with sugar in Table 1.24 is an intersting formulation for film-coatings. In this case, the film-forming and plastic properties of Kollidon VA 64 are combined with the protective and taste masking properties of sugar. Kollidon VA 64 not only acts as a film-forming agent, it also acts as a crystallization inhibitor that prevents the sugar from crystallizing during spraying and on the tablets. The coating can be applied in any thickness desired. 52

54 Table 1.24: Sugar film-coating with Kollidon VA Formulation of the spray suspension Sucrose 200 g Kollidon VA g Titanium dioxide 30 g Sicovit Iron oxide 15 g Macrogol g Talc 50 g Water ad 1200 g 2. Preparation Dissolve the sucrose, Kollidon VA 64 and macrogol 4000 in the water and suspend the other components. Pass through a colloid mill. 3. Coating conditions (Accela Cota 24) Batch size (tablet cores) 5.0 kg Amount of coating suspension 1.2 kg Inlet air temperature 45 C Outlet air temperature 36 C Nozzle 0.8 mm Coating pan speed 15 rpm Spray pressure 2.0 bar Spraying time (continuous) 50 min Quantity of film former applied 4 mg/cm Traditional sugar coating Kollidon 30 or Kollidon VA 64 Kollidon 30 and Kollidon VA 64 are also used in traditional sugar coating, as they reduce the rate of crystallization of the sugar, which in turn makes it possible to automate the coating process. Typically, about 10 % Kollidon (as a proportion of the sucrose) is used. Sugar coatings are particularly susceptible to cracking when they are applied to large batches of tablet cores that are dried rapidly. As most active ingredients are hydrophobic, Kollidon VA 64 and Kollidon 30 are useful as additives to prevent the tablet coating peeling during manufacture. Particularly when soluble dyes are used, Kollidon VA 64 and Kollidon 30 are useful in achieving an even distribution of the dye and preventing its migration, as well as increasing the capacity of the coating suspension for the dye. 53

55 Apart from its use in manual sugar coating, Kollidon VA 64 or Kollidon 30 makes it possible to automate the traditional sugar coating process. Table 1.25 gives a suitable formulation. Table 1.25: Spray suspension for automatic sugar coating 1. Formulation of the coating suspension Sucrose 76 g Kollidon 30 8 g Titanium dioxide 9 g Calcium carbonate 9 g Talc 29 g Colorant/pigment (e.g. Sicovit iron oxide) q.s. Glycerol 4 g Water 63 g 2. Procedure 40 kg of tablet cores with a weight of 420 mg were sprayed with 25 kg of the above suspension in a conventional coating pan under the following conditions: 3. Coating conditions Spray phase: Interval: Drying phase (warm air): Total coating time: 5 s 10 min 10 min 16 h Subcoating of tablet cores Kollidon VA 64 (Kollidon 30) Kollidon VA 64, which is much less hygroscopic and more plastic than povidone, is more suitable and more widely used for subcoating tablet cores or capsules than Kollidon 30 or Kollidon 25. In this application, it is used either to form a moisture barrier around the tablet core or capsule to prevent the entry of water during subsequent processing, or as an adhesion promoter to give tablet cores and capsules a hydrophilic surface for subsequent film-coating or sugar coating. The most important reasons for the application of a subcoating and for the functions of Kollidon VA 64 are summarized in Table

56 Table 1.26: Reasons for subcoating tablet cores and the function of Kollidon VA 64 in this application Reasons for subcoating Function of Kollidon VA 64 tablet cores Instability of the active ingredient towards water (hydrolysis) Chemical interactions between the active ingredients (e.g. vitamins) Presence of high-performance disintegrants Hydrophobic surface of the tablet core or capsule Dust formation (friability of the tablet cores) Formation of a barrier layer on the surface and in the pores Formation of a barrier layer on the surface and in the pores Formation of a barrier layer on the surface and in the pores Improvement in adhesion of subsequent coatings by hydrophilization of the surface Loose particles are bound to the surface of the tablet core Kollidon VA 64 (or Kollidon 30) is usually sprayed onto the cores as a 10 % solution in alcohol (e.g. ethanol or 2-propanol) during few minutes until an adequate thickeness is achieved Taste masking by coating of tablets Kollidon VA 64, Kollicoat Protect, Kollicoat IR A film-coating containing Kollidon VA 64 and sucrose is one of the simplest and most effective means of masking the unpleasant taste of tablets without compromizing drug release. An example of such a coating is given in Section This applies in even more to Kollicoat Protect. To demonstrate this application pseudo-ephedrine tablets were used. Pseudo-ephedrine hydrochloride is an active ingredient with a bitter taste; this is very much enhanced by its very good solubility. For this reason, it is suitable for use as a test substance in experiments designed to mask taste as it is immediately tasted if the tablets remain uncoated. Using direct compression technology, tablet cores containing 90 mg of active ingredient were produced (weight 300 mg, diameter 9 mm). 5 kg of these cores were coated with a white spray suspension of Kollicoat Protect in an Accela Cota 24 (Manesty) coating machine. Coatings of 10, 15 and 20 mg/cm 2 were obtained. The formulation for the spray suspension, the spraying conditions and the machine settings are summarized in Table The spraying time was able to be considerably shortened due to the higher spraying rate used. 55

57 Table 1.27: Taste masking film-coating with Kollicoat Protect for 5 kg of pseudo-ephedrine tablets (weight 300 mg, diameter 9 mm) Content [%] 1. Formulation of spray suspension Kollicoat Protect 12 Talcum 6 Titanium dioxide 2 Water 80 Total Coating conditions (Accela Cota 24, Manesty) Inlet air temperature 60 C Outlet air temperature 37 C Cores temperature 32 C Air flow 389 m 3 /h Spray pressure 2 bar Spray rate g/min Final drying 3 min, 60 C Quantity applied 10, 15 and 20 mg solids/cm 2 The effect of taste masking was tested subjectively; a tablet was placed in the mouth and the time noted for the first bitter taste to occur. The results shown in Table 1.28 show that a coating of 20 mg/cm 2 is adequate to mask the taste for more than one minute. Table 1.28: Taste masking effect of Kollicoat Protect on pseudoephedrine tablets Amount of coating used Time to occurrence of bitter taste Without coating < 1 sec. 10 mg/cm sec. 15 mg/cm sec. 20 mg/cm 2 78 sec. 56

58 1.6.9 Taste masking by coating of granules or crystals before tabletting Kollicoat SR 30 D The alternative to the coating of tablets of active ingredients with an unpleasant taste is the coating of the crystals or granules of such active substance before tabletting. For this purpose the film-former Kollicoat SR 30 D could be used. As this polyvinyl acetate polymer is insoluble in water, the optimum quantity and the composition of the formulation must be determined very carefully, to minimize the delay in drug release, though this delay can be reduced to some extent by adding hydrophilic polymers (e.g. Kollidon 30) or surfactants. Acetaminophen crystals, for example, have a bitter taste, but if 300 g of these crystals are coated with an dispersion of 150 g Kollicoat SR 30 D and 33.7 g Kollidon 30 in 210 g water in a fluidized bed granulator until the resulting granules are coated with 15% polyvinyl acetate and 11 % Kollidon 30, the bitter taste is masked for more than 2 minutes. Even after these acetaminophen granules are compressed into tablets with a little of microcrystalline cellulose, drug release is not much slower than from the uncoated substance (Fig. 1.21). Similar results were obtained with ibuprofen Released drug, % Tablets from uncoated crystals 20 Tablets from coated crystals (15% PVAc + 11% PVP) min Fig. 1.21: Release of taste masked acetaminophen tablets (from crystals coated with Kollicoat SR 30 D + Kollidon 30) 57

59 1.7 Colorants (pigments) Sicovit iron oxides Both in tablets and in tablet coatings, iron oxide pigments are finding increasing favour over the lakes of organic dyes, even though the colours that can be achieved are not quite as brilliant. Usually, one or two iron oxide pigments are combined with titanium dioxide to obtain the desired shade. If the tablets are to be made by direct compression, it is recommended to first mix the pigments with the lubricant (e.g. magnesium stearate), and to use this mixture as a lubricant. This ensures that the pigments are homogeneously distributed throughout the tablets. Table 1.29 shows a typical example of this application in the formulation for a vitamin B12 tablet. Table 1.29: Coloured vitamin B12 tablets (50 µg) 1. Formulations I. Cyanocobalamin gelatin coated 0.1 % 50.0 g Ludipress g II. Magnesium stearate 1.5 g Sicovit Iron oxide Yellow g Sicovit Iron oxide Red g 2. Procedure (direct compression) Prepare premix II, add to mixture I, pass through a 0.5 mm sieve and press with low compression force. 3. Tablet properties Weight 209 mg Diameter 8 mm Hardness 80 N Disintegration 10 min Friability < 0.1 % Colour homogeneous 58

60 Coating pigment suspensions are best stabilized with Kollidon 25 or Kollidon 30, as the example of a spray suspension formulation for couloured enteric film-coating shows in Table Table 1.30: Enteric film-coating of tablets with Sicovit Iron Oxide Red 30 (for 5 kg tablet cores, 9 mm diameter) 1. Formulation I. Pigment suspension: Titanium dioxide Talc Sicovit Iron Oxide Red 30 Kollidon 30 Water II. Polymer suspension: Kollicoat MAE 30DP Propylene glycol Water Total I + II: 6 g 48 g 6 g 6 g 120 g 600 g 18 g 396 g 1200 g 2. Preparation of the spray suspension I. Suspend the pigments and talc in the thoroughly stirred solution of Kollidon 30 and homogenize in a disk mill or in a colloid mill. II. Separately suspend Kollicoat MAE 30DP in the solution of propylene glycol. Add pigment suspension I to the thoroughly stirred polymer suspension II. Keep the suspension stirred throughout the coating process. 59

61 60

62 61

63 62

64 2. Modified-release solid dosage forms (Tablets, pellets and granules) 2.1 Enteric film-coatings with Kollicoat MAE grades General notes The copolymer products Kollicoat MAE 30 DP and Kollicoat MAE 100 P based on methacrylic acid and ethylacrylate only dissolve at ph values of 5.5 and above, and are used for enteric film-coatings for tablets, pellets, granules and capsules. Both the aqueous dispersion, Kollicoat MAE 30 DP and the powder, Kollicoat MAE 100 P can be processed easily in water, are impermeable to protons, ions and water, and have low hygroscopicity. It is not necessary to cure the tablets or capsules after coating. The dissolution in water in dependence of the ph is identical for both Kollicoat MAE grades. It is shown in Fig. 2.1 that the dissolution starts at ph Dissolution, mg/min ph Fig. 2.1: Dissolution of Kollicoat MAE grades in aqueous medium as a function of ph The powder Kollicoat MAE 100P is partly neutralized. Therefore it is possible to produce the polymer dispersion for manufacturing by stirring this powder into water without the addition of any alcaline substance. A further advantage of Kollicoat MAE 100P is that the dispersion obtained by this manner is 63

65 more compatible with other excipients and less sensitive about shearing forces in comparison with the commercial dispersion Kollicoat MAE 30DP which is not partly neutralized. As the Kollicoat MAE copolymer has a very low plasticity, always it is recommended to add a plasticizer like 1,2-propylene glycol or triethyl citrate. Fig. 2.2 shows the influence of different triethyl citrate concentrations on the elongation at break of this polymer. Most coating formulations with Kollicoat MAE grades given in this book contains about 15 % of 1,2-propylene glycol as plasticizer. The influence of 1,2-propylene glycol on the minimum film-forming temperature (MFT) of Kollicoat MAE is shown in Section Elongation at break, % % 15% 20% Triethyl citrate in the Kollicoat MAE polymer Fig. 2.2: Influence of triethyl citrate on the elongation of the Kollicoat MAE copolymer Enteric film-coating of tablets and capsules To obtain enteric tablets that meet the requirements of the pharmacopoeias (insoluble for 2 h at ph 1 and readily soluble at ph 6.8), the tablet cores should generally be coated with a amount of 3 6 mg solids/cm 2. A typical formulation of acetylsalicylic acid tablets coated with Kollicoat MAE grades and the machine settings for an Accela Cota 24 (Manesty) are given in Table 2.1. In this formulation, the 495 g of Kollicoat MAE 30 DP can be replaced directly with the equivalent quantity of g of the powder product, Kollicoat MAE 100 P plus the missing quantity of water contributed by the polymer dispersion. 64

66 Table 2.1: Enteric film-coating of acetylsalicylic acid tablets (for 5 kg of cores, 300 mg weight, 9 mm diameter) 1. Formulation I. Polymer suspension: Alternative I: Kollicoat MAE 30 DP 1,2-Propylene glycol Water Alternative II: Kollicoat MAE 100 P 1,2-Propylene glycol Water II. Pigment suspension: Titanium dioxide Talc Sicovit Iron Oxide Red 30 Water. Total (I + II): g 22.3 g g g 22.3 g g 4.9 g 39.6 g 4.9 g g 990 g 2. Procedure I. Mix 1,2-propylene glycol with water and stir in Kollicoat MAE 30DP or suspend Kollicoat MAE 100 P in 665 g of water, stir for 2 3 hours and add the propylene glycol. II. Suspend the pigments and talc in 103 g of well stirred water and homogenize in a disk mill or in a colloid mill. Add the pigment suspension II to the well stirred polymer suspension I. Stir the spray suspension obtained throughout the coating process. 3. Coating conditions (Accela Cota 24, Manesty) Inlet air temperature 50 C Outlet air temperature 37 C Core temperature 32 C Spray rate 40 g/min Spray pressure 2.0 bar Spraying time (continuous) 30 min Quantity of solids applied 3 4 mg/cm 2 3 mg of solids/cm 2 of the spray formulation as described in Table 2.1 were sprayed onto 5 kg of cores. Subsequently, the release of active ingredient from the coated tablets was determined after 2 hours of immersion in synthetic gastric juice and then in synthetic intestinal fluid and compared with that of uncoated cores in synthetic intestinal fluid only. Fig 2.3 shows that the tablets were fully gastric juice-resistant and that active ingredient release from the tablets after changing the medium was almost as fast as from the uncoated cores. 65

67 N HCI Phosphate buffer ph 6.8 Release of active ingredient, % Uncoated tablets (Phosphate buffer only) Coated tablets Time, min Fig. 2.3: Release of acetylsalicylic acid from tablets coated with Kollicoat MAE grades compared with uncoated cores Kollicoat MAE 100 P can also be applied in the form of a non-aqueous system, i.e. a solution in organic solvents such as a mixture of ethanol or 2-propanol and acetone Enteric coating of pellets and crystals Gastric juice-resistant (enteric) pellets or crystals are also produced for marketing as hard gelatine capsules; these are filled into the capsules. The main difference in comparison to the enteric coating of tablets is the needed total amount of gastroresistent polymer. This is explained by the higher surface of pellets and even higher surface of crystals. In the case of crystals the weight increase can be until 30 % of solids. In the following example of diclofenac pellets about 20 % of coating solids was applied. For this application test, uncoated diclofenac drug pellets were produced with the following composition: Sodium diclofenac 10 %, Kollidon VA %, microcrystalline cellulose 43.7 %, lactose monohydrate 43.7 %. The pellets, rendered spherical, had a diameter of mm. The spray suspensions containing both Kollicoat MAE grades were produced in the composition shown in Table 2.2 with a solid content of 22 % and a polymer content of 15 %. The indicated amounts and coating conditions were designed for coating 5 kg of pellets in a Kugelcoater of Hüttlin. 66

68 Table 2.2: Enteric film-coating of diclofenac drug pellets (for 5 kg of pellets) 1. Formulation of spray suspension I. Polymer suspension: Alternative I: Kollicoat MAE 30 DP 1,2-Propylene glycol Water Alternative II: Kollicoat MAE 100 P 1,2-Propylene glycol Water II. Pigment suspension: Titanium dioxide Talc Kollidon 30 Water. Total (I + II): g 67.5 g g g 67.5 g g 45.5 g g 22.5 g g g 2. Procedur I. Mix 1,2-propylene glycol with water and stir in Kollicoat MAE 30DP or suspend Kollicoat MAE 100 P in water, stir for 2 3 hours and add the propylene glycol. II. Suspend the pigments and talc in the well stirred solution of Kollidon 30 and homogenize in a disk mill or in a colloid mill. Add the pigment suspension II to the well stirred polymer suspension I. Stir the spray suspension obtained throughout the coating process. 3. Coating conditions (Kugelcoater HKC 5 TJ, Hüttlin) Inlet air temperature 60 C Outlet air temperature C Spray rate 45 g/min Spraying time (continuous) 100 min Quantity of solids applied 3 mg/ cm 2 The release of the enteric sodium diclofenac pellets produced according to Table 2.2 was tested by placing the coated pellets in artificial gastric juice for a period of 2 hours and subsequently in artificial intestinal fluid. During the first 2 hours (ph 1) no drug release was observed and during the following 55 min almost 100 % of diclofenac sodium were dissolved. 67

69 2.2 Sustained-release coating of pellets Pellet film-coating with Kollicoat SR 30D Plasticity, a low minimum film-forming temperature and an absence of tack make Kollicoat SR 30 D (30 % dispersion of polyvinyl acetate and Kollidon 30 in the ratio 9:1 in water) an excellent film-forming agent for sustainedrelease pellets. For this application drug pellets or drug layered nonpareilles can be used. In the unlikely event that a plasticizer is required, 5 10 % 1,2-propylene glycol is quite adequate. The pellets obtained can be marketed as such or filled into hard gelatin capsules. The formulation for ambroxol sustained-release pellets in Table 2.3 is a typical example of this application of Kollicoat SR 30 D on drug layered nonpareilles which were produced by coating commercially available placebo pellets with a coating of the active ingredient ambroxol hydrochloride and Kollicoat IR or HPMC g of these drug layered nonpareilles were film coated with 5, 10, 15 and 20 % of a colourless film coating in a fluidized bed granulator GPCG1 (Glatt) using a process according to Wurster and the amounts and spraying conditions listed in Table 2.3. To prepare the spray suspension, plasticizer triethyl acetate was mixed with water and Kollicoat SR 30D stirred in. Separately, talcum was suspended in water and homogenized with a high-speed stirrer. The talcum suspension was then stirred into the polymer suspension. During the entire spraying process the spray suspension thus obtained was continuously stirred. Table 2.3: Sustained-release coating of ambroxol-hcl pellets 1. Formulation of colourless spray suspension I. Kollicoat SR 30 D 533 g Tritethyl citrate 16 g Water 433 g II. Talcum 56 g Water 100 g 2. Uncoated pellets (batch size) 800 g 3. Coating conditions (Fluidized bed granulator Glatt CPCG1) Inlet air temperature C Outlet air temperature C Pellet temperature C Spray pressure 1.2 bar Amount of inlet air 90 m 3 /h Spray nozzle 1.2 mm Spraying time 220 min Subsequent drying 15 min/40 C Coating amount applied 5 20 % solids 68

70 Measurement of the release of active ingredient ambroxol-hcl from the pellets was carried out under the following conditions: 0 24 h in phosphate buffer ph 7.4 at 37 C and 100 rpm. Active ingredient release was measured using coating amounts between 5 and 20 %. Fig. 2.4 shows that between 15 and 20 % coating there is no strong difference and that in this case a coating of about 10 % would be appropriate for active ingredient release over a period of 24 h. 100 Release of active ingredient, % % coating 10% coating 15% coating 20% coating Time, h Fig. 2.4: Release of sustained-release ambroxol-hcl pellets Pellet film-coating with Kollicoat EMM 30D Kollicoat EMM 30D is the 30 % aqueous dispersion of polyacrylate (ethyl acrylate methyl methacrylate 2:1 copolymer) for sustained-release dosage forms that also features high plasticity and a good retarding effect. The one disadvantage of Kollicoat EMM 30D as a film former is its tackiness. For this reason, practically all formulations must include an anti-tack agent. The most widely used agent of this type is talcum; however, microcrystalline cellulose (MCC), hypromellose and simethicon are also suitable. However, MCC and hypromellose have some influence on the sustained-release effect of the polymer. This is schematically illustrated in Fig In the case of hypromellose 2910, type 3 mpa.s (HPMC), this side-effect is strongest; for, as fast as the tackiness decreases with increase in concentration, the more the sustained-release effect of Kollicoat EMM decreases due to its pore forming effect. In the case of microcrystalline cellulose (MCC), the sustained-release 69

71 effect is not so strongly reduced but its influence on tackiness is considerably less than in the case of hypromellose. The fact that talcum in concentrations normally used has practically no effect on the sustained-release effect explains why it is the most widely used anti-tack agent. The effect of talcum can be enhanced in the case of Kollicoat EMM 30D films by combining with simethicon. Microcryst. Cellulose Hypromellose Talc (+ simethicone) Sustained release effect Concentration of antiadhesive Tackiness Fig. 2.5: Effect of some anti-tack agents in pellet coating formulations with Kollicoat EMM 30 D Kollicoat EMM 30 D is processed for the sustained-release pellet coating by the same methods as Kollicoat SR 30 D. Plasticizers are never required. Also for this application drug pellets or drug layered nonpareilles can be used. 70

72 2.3 Sustained-release tablets Direct compression Kollidon SR Kollidon SR is the spray-dried form of polyvinyl acetate stabilized by the addition of 19 % Kollidon 30, and is a free-flowing powder. This makes it ideal for direct compression. When it is compressed, it forms a matrix structure from which the active ingredient is released gradually. The Kollidon 30 also forms pores in this matrix from which the active ingredient is released mainly by diffusion. Other excipients that swell or dissolve in water such as lactose monohydrate, Ludipress LCE or Kollidon CL-M can also be considered as pore-formers. The quantity of Kollidon SR required to extend drug release over a period of hours depends mainly on the particle size and the solubility of the active ingredient. For a soluble active ingredient more than the double concentration of Kollidon SR would needed in the tablet in comparison with a slightly soluble active ingredient. The usual amount of Kollidon SR lies in the range of % of the weight of the tablets. The smallest quantity required to form an adequate matrix usually is about 15 %, even if the active ingredient is insoluble (e.g. theophylline) and present in a low dosage. It is usually necessary to include a hydrophilic component such as lactose or a pore-former such as Kollidon CL or Kollidon 30 with insoluble active substances. The following concentrations of Kollidon SR in the tablets can be taken as a guide in most cases: Soluble drugs: % Less soluble drugs: % Sparingly soluble drugs: % On the other hand the variation of the quantity of Kollidon SR in the tablet can be used for the adjustment of the release profile of the tablet of a given active ingredient. Fig. 2.6 shows the effect of using different quantities of Kollidon SR on the release of caffeine, a soluble active ingredient. 100 Released drug (%) mg Kollidon SR 120 mg Kollidon SR 160 mg Kollidon SR Time (h) Fig. 2.6: Influence of the amount of Kollidon SR on the release of caffeine sustained-release matrix tablets (Caffeine 160 mg, Kollidon SR mg, Aerosil 200 (Degussa) 3.4 mg, magnesium stearate 1.6 mg) 71

73 To demonstrate the application of Kollidon SR in a sustained-release matrix tablet of a soluble active ingredient obtained by direct compression diclofenac sodium was selected. Table 2.4 shows the formulation for 100 mg active ingredient. It contains almost 50 % Kollidon SR. Table 2.4 Formulation of diclofenac sodium sustained-release matrix tablets with Kollidon SR 1. Formulation of tablets Weight [g] [%] Diclofenac sodium (Irotec) Kollidon SR Aerosil 200 (Degussa) Magnesium stearate Manufacture (Direct compression) Pass all ingredients through a sieve, mix for 10 min and press on a rotary press with a medium compression force. 3. Tablet properties Diameter 8 mm Weight 206 mg Hardness 195 N Friability < 0.1 % The release profile of diclofenac sodium of the tablets of Table 2.4 was not completely 24 hours as shown in Fig The main reason was the relative fine particle size of the active ingredient used in this formulation. % drug released Medium: 0.08 N HCl (0-2 h), phosphate buffer ph 6.8 (2-16 h) hours Fig. 2.7: Diclofenac sustained-release matrix tablets (Direct compression) 72

74 Since the needed concentration of Kollidon SR is relatively high for soluble active ingredients it would be even more suitable for less soluble active substances. Table 2.5 shows an example of theophylline sustained-release matrix tablets with 21 % Kollidon SR. This concentration could be lower by reduction of the amount of the pore former Ludipress LCE in the formulation. Table 2.5 Formulation of theophylline sustained-release matrix tablets with Kollidon SR 1. Formulation of tablets Weight [g] [%] Theophylline gran. (BASF) Kollidon SR Ludipress LCE Magnesium stearate Manufacture (Direct compression) Pass all ingredients through a sieve, mix for 10 min and press on a rotary press with a compression force of about 11 kn. 3. Tablet properties Diameter 19.0 x 8.5 mm Weight 928 mg Hardness 172 N Friability < 0.1 % Fig. 2.8 shows that the release of the theophylline tablets of Table 2.5 is even more extended than 24 hours. Therefore the concentration of Kollidon SR could be reduced to obtain an release profile of about 24 hours. drug release [%] medium: 0.08 N HCI (0-2 h) phosphate buffer ph 6.8 (2-16 h) time [h] Fig. 2.8: Release of theophylline sustained-release tablets with Kollidon SR (Formulation see Table 2.5) 73

75 2.3.2 Sustained-release matrix tablets obtained by wet granulation and compression Kollicoat SR 30D In contrast to Kollidon SR, Kollicoat SR 30D is an aqueous dispersion of 27 % polyvinyl acetate and 2.7 % Kollidon 30. It is intended not for direct compression, but for wet granulation of sustained-release matrix tablets or for film-coatings. In the case of sustained-release tablets, the minimum quantity of matrix former required is generally much less than with Kollidon SR, as it does not contain 20 % of the pore former Kollidon 30. In this technology, the active ingredient, with or without filler, is granulated with Kollicoat SR 30D and, subsequent to the addition of further excipients like extragranular fillers and/or lubricants, compressed to matrix tablets with controlled-release properties. When using standard amounts of polyvinyl acetate of 5 30 % in the granules, a matrix structure is formed on compression that encloses the particles of active ingredient. Subsequent to penetration of gastric juice or intestinal fluid into the matrix, the active ingredient is slowly dissolved; it then diffuses through the matrix at a controlled speed. Like in the case of Kollidon SR the drug release of tablets produced with Kollicoat SR 30D is completely independent on the ph and on the ionic strength of the dissolution medium. An other important property of this polymer is its plasticity which avoids any influence of the tabletting compression force on the drug release. This is demonstrated in Fig. 2.9 by means of a tablet of the active ingredient propranolol hydrochloride. The dissolution of propranolol-hcl before tabletting and after tabletting applying low, medium and high compression forces did not show any significant difference. The needed amount of Kollicoat SR 30 D for the sustained release of hours depends mainly on the solubility of the active ingredient. Its particle size also can have an influence but it is not so strong as in the case of direct compression with Kollidon SR. The usual amounts of polyvinyl acetate in the granules lies in the range of 5 15 % for sparingly soluble or insoluble active ingredients and % for soluble or very soluble active substances. Table 2.6 shows as a typical example of a soluble active ingredient that for propranolol hydrochloride only about 16 % of polyvinyl acetate are required in the granules as a proportion of the active ingredient which represents about 8 % of the finished tablet. 74

76 Table 2.6: Sustained-release matrix tablets of propranolol hydrochloride (160 mg) 1. Formulation I. Propranolol-HCl 160 mg II. Kollicoat SR 30D 110 mg Triethyl citrate 3 mg III. Microcrystalline cellulose 200 mg Magnesium stearate 2 mg 2. Procedure (wet granulation in a fluidized bed system) Granulate I with the mixture II in the fluidized bed (inlet temperature about 55 C, outlet temperature about 30 C), mix with the components III and press with low compression force. 3. Tablet properties Weight 400 mg Diameter 11 mm Friability < 0.1 % Drug release see Fig. 2.9 The sustained release of the propranolol-hcl tablets of Table 2.6 is demonstrated in Fig There is neither an influence of the tabletting process nor an influence of the compression force in the range of 5 to 25 kn. The granules before tabletting gave almost the same release profile as the final tablets. 100 Drug release, % Granules before tabletting Compression force 5 kn Compression force 15 kn Compression force 25 kn Time, h Fig. 2.9: Influence of the compression forces on the release of propranolol- HCl matrix tablets (formulation see Table 2.6) 75

77 In a similar formulation of propranolol hydrochloride as given in Table 2.6 the influence of the granulation technology was investigated, the parameters selected being tablet hardness and release of the active ingredient. It was found that the traditional mixer granulation produces tablets of considerably less hardness than with fluidized bed granulation. Fig 2.10 shows that the sustained-release effect with fluidized bed granulation is somewhat greater, i.e. with traditional mixer granulation the active ingredient propranolol is released a little quicker. In order to compensate for this, a little more sustainedrelease polymer is required in order to achieve the same effect as with fluidized bed granulation. In other examples such influence of the granulation technology on the drug release was even stronger. Therefore, fluidized bed granulation is the recommended technology for sustained-release matrix tablets. 100 Release of active ingredient, % Mixing granulator Fluidized bed granulation Time, h Fig. 2.10: Influence of granulation technology on the release of propranolol- HCl sustained-release matrix tablets with Kollicoat SR 30D The next example of a sustained-release matrix tablet with Kollicoat SR 30D is given in Table 2.7 and based on the insoluble active ingredient carbamazepine. In this case about 7 % polyvinyl acetate is used in the granules and final tablets. 76

78 Table 2.7: Carbamazepine sustained-release matrix tablets (200 mg) 1. Formulation I. Carbamazepine (Sintetica) 200 g Lactose monohydrate 148 g Kollidon CL-M 20 g II. Kollicoat SR 30 D 99 g III. Aerosil 200 (Degussa) 2 g Magnesium stearate 2 g 2. Procedure of wet granulation in Aeromatic Strea-1 (Niro) Granulate mixture I with Kollicoat SR 30 D (II) in a top spray fluidized bed, mix with the components of III and press with medium compression force 3. Tablet properties Weight 407 mg Diameter 11 mm Form biconvex Hardness 136 N Friability < 0.1 % The carbamazepine in the tablets formulated as described in Table 2.7 is released over a period of 16 hours (see Fig. 2.11). If the pore former Kollidon CL-M is not included in this formulation the release of the active ingredient after 16 hours would be only about 40 %. Therefore this is a typical example of function and need of a pore former in sustained-release matrix tablets of insoluble active ingredients. 100 Drug, dissolved, % Medium: 0.08 N HCl (0-2 h), phosphate buffer ph 6.8 (2-16 h) hours Fig. 2.11: Release of carbamazepine controlled-release matrix tablets with Kollicoat SR 30 D 77

79 Kollicoat EMM 30D Kollicoat EMM 30 D is an aqueous dispersion of polyacrylate (copolymer of ethylacrylate and methyl methacrylate 2+1) and is used in much the same manner as Kollicoat SR 30 D. It is essential to reduce the greater tack of Kollicoat EMM 30 D by adding an antiadhesive (for details see Section 2.2.2). The formulations are very similar to those of Kollicoat SR 30D but the quantities of Kollicoat EMM 30 D required for the manufacture of sustainedrelease matrix tablets via wet granulation often can be somewhat less than those for Kollicoat SR 30 D, as its sustained-release effect is greater. Generally a plasticizer never is needed for formulations of Kollicoat EMM 30D because its plasticity is very high. One of the goals of the theophylline tablet formulation given in Table 2.8 was to demonstrate how, by varying the amount of Kollicoat EMM polymer, the release profile of the active ingredient can be influenced. The active ingredient theophylline was mixed with a filler/pore former and this mixture sprayed with 5.0 and 7.5 % solid Kollicoat EMM, based on the weight of granulate, directly in an Aeromatic Strea-1 (Niro) fluidized bed granulator. The dry granules were mixed with magnesium stearate lubricant and flowability agent Aerosil 200 (Degussa) for 10 minutes and then sieved. The mixture was compressed to 19 x 8.5 mm oblong tablets of approx. 800 mg weight with an active ingredient of approx. 400 mg using a compression force of 18 kn. Table 2.8: Formulations and granulation conditions for theophylline sustained-release matrix tablets 1. Formulations No. 1 No. 2 (5.0 %) (7.5 %) I Theophylline powder (BASF) 400 mg 400 mg Lactose monohydrate 360 mg 340 mg II Kollicoat EMM 30 D 133 mg 200 mg (= 40 mg solids) (= 60 mg solids) III Magnesium stearate 4 mg 4 mg Aerosil 200 (Degussa) 4 mg 4 mg Tablet weight 808 mg 808 mg 2. Granulation settings (fluidized bed granulator, top-spray method) Inlet air temperature 55 C Outlet air temperature: C Nozzle diameter 0.8 mm Spray rate Approx. 10 g/ml Spray pressure 2 bar 78

80 The amount of Kollicoat EMM 30D required in the theophylline sustainedrelease tablets is very low due to the insolubility of theophylline if no pore former is used. As can be seen in Fig 2.12, for the particle size of theophylline (powder, BASF) used, the amount of solid Kollicoat EMM of 5 %, based on the weight of granulate, would be just right for release of active ingredient over a period of 24 h. This amount should if at all possible not be smaller as it might prevent the formation of the right matrix structure. 100 Release of active ingredient, % % Kollicoat EMM polymer 7.5% Kollicoat EMM polymer Time, h Fig. 2.12: Influence of the amount of Kollicoat EMM on the release of theophylline sustained-release matrix tablets Compression of sustained-release pellets to tablets Kollicoat SR 30D, Kollicoat EMM 30D As tablets are the most popular and best accepted drug form, sustainedrelease pellets can also be compressed to tablets instead of being filled into hard gelatine capsules. However, in the case of pellet compression, the plasticity of the coating is even more important as these rounded particles have to be deformed even more in order to produce tablets with a sustainedrelease matrix and no hollow spaces. Thus, it is not possible to compress sustained-release pellets coated with the popular ethyl cellulose to tablets. Even if 25 % triethyl acetate was added as plasticizer to the ethyl cellulose, the release profile was significantly altered due to the mechanical stress of compression. The loss of sustained-release effect brought about by compression is disproportionately high and hence unacceptable in practice. 79

81 If the same pellets are coated using the identical amount of Kollicoat SR film instead of ethyl acetate containing only 10 % instead of 25 % of triethyl acetate plasticizer and if these are subsequently compressed in the same way and formulation to tablets the release effect is not reduced as a result of the mechanical stress of compression. Electron microscopic photos showed that the pellets in this case were not destroyed but only deformed. For this reason, Kollicoat SR 30D and also Kollicoat EMM 30D can be regarded as excellent film formers for the technology of preparing tablets from sustained-release pellets. The sustained-release pellets can be compressed to tablets with various fillers; however, release is not always uniform as the pores and dissolution speeds tend to vary. Based on experience gained, the differences are not very great. Strongly swelling or strongly hydrophilic excipients such as micronized crospovidone (e.g. Kollidon CL-M) accelerate release. In the case of sparingly soluble active ingredients such as theophylline or carbamazepine, hydrophilic fillers like lactose monohydrate in pure or granule form (Ludipress LCE) or even Kollidon CL-M are perhaps more suitable. For readily soluble active ingredients, microcrystalline cellulose could be the substance of choice. To demonstrate this application of Kollicoat SR 30D the ambroxol sustainedrelease pellets as described in Section 2.2.1, with coatings of 10 and 20 % solids, were compressed to biplanar tablets using direct tabletting technology in the formulation given in Table 2.9. Table 2.9: Formulation of ambroxol-hcl sustained-release tablets from pellets with Kollicoat SR 30D Table 2.9: Formulation of ambroxol-hcl sustained-release tablets from pellets with Kollicoat SR 30D 1. Formulation (direct compression) Ambroxol-HCl sustained-release pellets with Kollicoat SR 30D (as described in Section 2.2.1) Microcrystalline cellulose Magnesium stearate g g 2.5 g 2. Tablet properties (compression force: 15 kn Weight Diameter Hardness 400 mg 10 mm about 100 N The release of ambroxol-hcl from the sustained-release tablets produced according to Table 2.9 was not quite as linear as the sustained-release pellets prior to compression (c.f. Section 2.2.1); however, they produced release of active ingredient over a period of 24 h. The curve of the tablets made from pellets with 20 % coating was somewhat flatter than that with 10 % (Fig. 2.13). 80

82 Release of active ingredient, % % coating 20% coating Time, h Fig. 2.13: Release of ambroxol-hcl sustained-release tablets produced from pellets with 10 and 20 % Kollicoat SR coating Sustained-release film-coating of tablet cores Kollicoat SR 30D Normally, the manufacture of sustained-release tablets by coating instantrelease tablet cores with a sustained-release coating is avoided; this is because the risk is too high of the active ingredient being released too quickly due to incomplete coating or, especially, damage to the coating. Using the example of sustained-release tablets containing metoprolol tartrate, propranolol hydrochloride or pseudo-ephedrine hydrochloride, it was, however, proven that this particular risk can be excluded in the case of Kollicoat SR 30D as a film former. In this way, a very simple system for achieving sustained release is possible. This is mainly due to the plasticity and elasticity of Kollicoat SR films, which enable the films to self-repair damage so that release remains unaffected. In addition, the film will not rupture should the core begin to swell during storage or during release of the active ingredient. To demonstrate this effect, Table 2.10 shows the elongation at break of isolated films containing 5 % triacetin and 10 % 1,2-propylene glycol as plasticizers in comparison with other sustainedrelease film formers ethyl cellulose and ammonium methacrylate co-polymer. The differences are so great that the surprising results obtained with Kollicoat SR 30D become understandable. 81

83 Table 2.10: Elongation at break of film formers with plasticizers (23 C, 54 % relative humidity) Sustained release Elongation at break film former 5 % triacetin 10 % propylene glycol Kollicoat SR 30D 188 % 300 % Ethyl cellulose dispersion 5.4 % 5.7 % Ammonium methylacrylate < 2.0 % < 2.0 % co-polymer In the coating formulation of metoprolol sustained-release tablets given in Table 2.11, the two co-polymers Kollicoat SR 30D and Kollicoat IR were combined in a ratio of 4:1 in order to increase the elasticity of the film. Experiments carried out with similar formulations containing propranolol-hcl and pseudo-ephedrine-hcl showed that the release profile could be altered by varying the ratio. The higher the proportion of soluble polymer Kollicoat IR, the more quickly the active ingredient was released. To produce the instant-release tablet cores, 4 kg of metoprolol tartrate were granulated with an aqueous solution of 100 g Kollidon 30 as binder, dried, sieved and mixed for 10 minutes with the other excipients (3200 g dicalcium phosphate, 80 g talcum, 60 g Aerosil 200 (Degussa) and 80 g magnesium stearate). The mixture was then compressed to biconvex cores with a weight of approx. 390 mg. 5 kg of the metoprolol tartrate cores were coated with a red spray suspension of Kollicoat SR 30D in an Accela Cota 24 (Manesty). Table 2.11 lists the formulation of the spray suspension and the conditions of the filmcoating process. To prepare the spray suspension, the pigments iron oxide and titanium dioxide were suspended with talcum in an aqueous solution of Kollidon 30 and Kollicoat IR and homogenized. The pigment suspension was stirred into the separately prepared aqueous mixture of triacetin and Kollicoat SR 30D. Kollidon 30 in this case served as a suspension stabilizer to prevent sedimentation and agglomeration of the pigments. Kollicoat IR is a very flexible film former that can also function as a pore former. 82

84 Table 2.11: Red spray suspension and spraying conditions for sustained-release film-coating of metoprolol cores 1. Spray suspension Kollicoat SR 30D 43.5 % Triacetin 0.7 % Kollicoat IR 3.3 % Kollidon % Titanium dioxide 0.5 % Sicovit red iron oxide 0.5 % Talcum 3.5 % Water 47.5 % 2. Coating parameters (Accela Cota 24, Manesty) Batch size 5 kg Inlet air temperature 50 C Tablet core temperature 35 C Spray pressure 2.0 bar Spray rate 22 g/min Amount applied (solid) 4, 6 and 10 mg/cm 2 The release of metoprolol tartrate was determined at three different applied amounts of coating. Measurement took place under the following conditions: 0 2 h in 0.08 M hydrochloric acid, 2 24 h in phosphate buffer of ph 6.8, 37 C and 50 rpm. Fig shows that, for release over a period of 24 h, a coating of 10 mg solid per cm 2 of tablet surface is appropriate. The S-curve is brought about by the fact that it takes some time for the water to penetrate the film and for the active ingredient to begin to dissolve before diffusing through the film to the exterior. The thicker the film, the stronger the affect achieved. 83

85 100 Release of active ingredient, % Uncoated cores 4 mg coating/cm 2 6 mg coating/cm 2 10 mg coating/cm Time, h Fig. 2.14: Release of metoprolol tartrate from sustained-release tablets as a function of coating thickness of Kollicoat SR 30D In order to investigate the sensitivity of the coating to mechanical stress and damage, two methods were selected that could well be described as being drastic in nature. In the first method a friability test the coated tablets were subjected to 500 revolutions in a friability apparatus with a falling height of 15 cm; thereafter, they were allowed to fall 20 times from a height of 1.5 m onto a stone floor. In the second method, the tablets were punctured with a needle in such a way that the coating was completely penetrated. Subsequent to both methods, the influence of release of active ingredient was determined. The results obtained were surprising, to say the least. In comparison with untreated tablets, not the slightest difference in release was observed (Fig 2.15). In the case of the punctured tablets, there must be some sort of mechanism whereby the damage is repaired. In this case, it is the high degree of plasticity that exists in the aqueous test medium that then, due to the swelling of the coating, closes off the holes. 84

86 100 Release of active ingredient, % Untreated tablets After friability testing Punctured tablets Time, h Fig. 2.15: Influence of mechanical stress and damage to the coating of metoprolol sustained-release film tablets on the release of active ingredient 85

87 2.4 Plasticizers Propylene glycol 1,2-Propylene glycol is nowhere near as effective a plasticizer as other traditional compounds such as triethyl citrate, but its adverse effect on drug release is less. This is particularly important with tablet coatings that dissolve in gastric juice and tablet coatings that do not. Furthermore 1,2-propylene glycol has no negative influence on the tackeniss of the coating (see Fig. 2.17). In concentrations of % as a proportion of the film-forming agent, 1,2-propylene glycol considerably reduces the minimum film-forming temperature (MFT). Fig shows the effect of adding 1,2-propylene glycol to Kollicoat MAE. MFT [ C] % 10% 15% Propylene glycol in Kollicoat MAE Fig. 2.16: Influence of 1,2-propylene glycol on the minimum film-forming temperature of Kollicoat MAE Typical examples of applications of 1,2-propylene glycol in formulations for tablet coatings are given in the Section of enteric coatings with Kollicoat MAE grades. 86

88 2.4.2 Macrogol as plasticizer Lutrol E 400 Liquid and solid macrogols such as Lutrol E 400 can also be used as plasticizers, though relatively large quantities of some 20 %, as a proportion of the film-forming agent, are required. The tackiness of films is an important property in the practical application of polymer coating. In the case of Kollicoat SR 30D films, this was investigated using the Hoessel method. Simultaneously, the influence of various concentrations of the plasticizers macrogol, 1,2-propylene glycol, triethyl citrate and triacetin was determined. The results of this investigation are shown in Fig. 2.17, where it can be seen that macrogol and 1,2-propylene glycol have no negative influence on the tackiness. However, in the case of the other two plasticizers at a concentration of 10 %, based on the polymer, the tackiness, also perceptible by the finger test, exceeded the limit of PVAc without plastic 5% Plasticizer in PVA 10% Plasticizer in PVA 2 1 Tacky Non-tacky 0 Without Propylene glycol Macrogol Triethyl citrate Triacetin Fig. 2.17: Influence of different plasticizers on the tackiness of polyvinyl acetate. 87

89 2.5 Mucoadhesives for buccal tablets Kollidon VA 64, Kollidon 30, Kollidon 90 F Both povidone (e.g. Kollidon 30 or Kollidon 90 F) and particularly copovidone (Kollidon VA 64) are suitable for use as mucoadhesives in buccal tablets. Mucoadhesive buccal tablets containing povidone or copovidone are typically used to administer such drugs as flurbiprofen, hormones, nicotine, morphine and verapamil. Table 2.12 gives basic formulations for a mucoadhesive tablet that was developed for morphine sulphate (20 mg). In this formulations, Kollidon VA 64 was found to be far superior to Kollidon 30 or Kollidon 90 F, particularly as the mucoadhesive strength of the tablets made with it was many times higher. Table 2.12: Mucoadhesive buccal tablet with Kollidon VA 64 (basic formulations) 1. Formulations No. 1 No. 2 I. Active ingredient (e.g. morphine sulphate) q.s. q.s. Lactose monohydrate 76 g 76 g Carbopol 934 (Goodrich) 4 g Carbopol 980/ (Goodrich) 4 g Kollidon VA g 19 g II. Ethanol 96 % 15 g 10 g III. Magnesium stearate 1 g 1 g 2. Procedure (wet granulation) Vigorously mix the components in I, granulate mixture I with ethanol II, pass through a 0.8 mm sieve, dry, sieve again through a 0.5 mm sieve, mix with the component III and press into tablets using medium compression force. 3. Tablet properties (Formulations No. 1 and No. 2) Diameter 8 mm Weight 200 mg Hardness > 180 N Disintegration > 30 min Friability < 0.1 % 4. Mucoadhesive strength (in vitro) One drop of human saliva was placed on a glass plate and a tablet was placed on this drop. After 7 min the force (N) was measured needed to pull the tablet off the glass plate perpendicularly: Formulation No. 1: about 7 N Formulation No. 2: about 3 N 88

90 89

91 90

92 3. Soft gelatin capsules 3.1 Carriers, solvents Lutrol E 300, Lutrol E 400, Lutrol E 600 Macrogols, usually in the form of liquid or semisolid mixtures, are used as carriers and solvents in soft gelatin capsules. Macrogols, e.g. mixtures of the Lutrol E grades, have the advantage over the normally used oils that they are hydrophylic and therefore tend to enhance the bioavailability of the embedded or dissolved drug. Nifedipine and temazepam are typical examples of drugs for which macrogols can be used as a carrier in soft gelatin capsules. 1,2-Propylene glycol Apart from glycerol, the most widely used solvent in soft gelatin capsules, it is also possible to use anhydrous 1,2-propylene glycol alone or, as is often done, in combination with glycerol. Typical examples of drugs with which 1,2-propylene glycol can be used in soft gelatin capsules are ibuprofen, cyclosporin and vitamins. 91

93 3.2 Solubilizers in soft gelatin capsules Cremophor RH 40, Cremophor EL Macrogolglycerol ricinoleate 35 and macrogolglycerol hydroxystearate 40 (Cremophor EL and Cremophor RH 40) are used as nonionic solubilizers in soft gelatin capsules to solubilize the active ingredient or to improve the release and bioavailability of active substances (see also Section 1.4.5). Because of the good miscibility and solubility of these solubilizers, their use does not depend on the carrier. This can be a vegetable oil or a specific triglyceride made from a vegetable oil (e.g. for vitamin capsules), or it can consist of macrogol, glycerol and/or 1,2-propylene glycol (e.g. for ibuprofen, cyclosporin or vitamin capsules). 92

94 3.3 Antioxidants in soft gelatin capsules alpha-tocopherol The fat-soluble antioxidants ascorbyl palmitate and alpha-tocopherol are used in soft gelatin capsules to stabilize oxidation-sensitive active ingredients. The quantity of alpha-tocopherol used usually lies in the range of %. Typical examples of this application of alpha-tocopherol are in capsules containing vitamins, carotenoids, omega fatty acids, isotretinoin and cyclosporin. This use is concentrated on capsules in which the carriers are vegetable oils and fatty acid glycerides. 93

95 3.4 Colorants in soft gelatin capsules Sicovit Iron oxides Though soft gelatin capsules, unlike the hard variety, are not always coloured, the use of colorants in this sector is not unimportant. As in the case of tablets, (see Sections 1 and 2) pigments are increasingly used for this dosage form. The iron oxide and titanium oxide pigments are the most widely applied. 94

96 95

97 96

98 4. Solutions 4.1 Solubilization for oral and topical use Surfactants as solubilizers Cremophor RH 40, Cremophor EL The preparation of a microemulsion with the aid of non-ionic solubilizers is a traditional method of solubilizing active ingredients of low solubility. In this method, they are incorporated in the surfactant micelles which are so small that they cannot be seen with the naked eye. The comparison of different non-ionic ethoxylated surfactants in Table 4.1 shows that the formation of a clear microemulsion or of a turbid macroemulsion does not depend on the degree of ethoxylation (ethylene units per molecule) but appearantly on the content of the free macrogol. All tested surfactants having a content of free macrogol lower than 6 % are emulsifiers. All non-ionic solubilizers like macrogolglycerol hydroxystearate 40 or macrogolglycerol ricinoleate 35 (Cremophor RH 40 or Cremophor EL) contain more than 12 % of free macrogol. An indirect proof of this theory was given by the extraction of the free macrogol from a solubilizer like Cremophor RH40 or Solutol HS15. After such elimination of the free macrogol part the solubilizing properties of the product are lost. The explanation is the formation of mixed micelles which have a stronger solubilization effect than normal micelles particularly if the free macrogol is combined with glycerol or sorbitol. Table 4.1: Degree of ethoxylation and content of free macrogol in some surfactants Surfactant Degree of Content of ethoxylation free macrogol (EO units per molecule) Emulsifiers (macroemulsion) Macrogol cetostearyl ether % Macrogol lauryl ether % Macrogolglycerol hydroxystearate % Solubilizers (microemulsion) Macrogol hydroxystearate % Polysorbate % Macrogolglycerol ricinoleate % Macrogolglycerol hydroxystearate % 97

99 The two products Cremophor RH 40 and Cremophor EL are excellent solubilizers for the oral and topical use. This applies particularly to Cremophor RH 40 as its odour and taste in aqueous solutions is very low. The principle of solubilization in a microemulsion is useful for lipophilic and strongly hydrophobic substances. Typical examples are the fat-soluble vitamins A, D, E and K1, antimycotics such as miconazole, ethereal oils and constituents of these, fragrance oils, buccal antiseptics such as hexeditine and certain drugs such as ciclosporin, simethicone and tramadol. In addition, many topical and buccal cleansing and antiseptic solutions also contain Cremophor RH 40 as it acts as a detergent at the point of application. As a typical example of a buccal application of Cremophor RH 40, Table 4.4 (Formulation No. 1) gives a formulation for a mouth-wash containing alpha-bisabolol, the active principal of camomile. As an example of oral applications of Cremophor RH 40, Table 4.2 gives a formulation for a multivitamin syrup and Table 4.11 a formulation for vitamin A + E drops. The two formulations in Tables 4.2 and 4.4 demonstrate that the solubilizer must always be heated with the lipophilic active before this mixture is mixed into the hot water as the continuous phase. 98

100 Table 4.2: Multivitamin syrup (1 2 RDA/20 ml) 1. Formulation I. Vitamin A palmitate 1.7 Mio. I.U./g (BASF) 10.0 mg Vitamin D 40 Mio. I.U./g 0.05 mg Vitamin E acetate (BASF) mg Butylhydroxytoluene 2.0 mg Cremophor RH g II. Water 10.0 g III. Sucrose 45.0 g Methylparaben mg Citric acid 80.0 mg IV. Glycerol 9.6 g Water 25.0 g V. Thiamine hydrochloride 15.0 mg Riboflavin 5 -phosphate sodium 15.0 mg Nicotinamide 55.0 mg Pyridoxine hydrochloride 15.0 mg Ascorbic acid, crystalline mg Sorbic acid mg 1,2-Propylene glycol 5.0 g Total amount 100 g 2. Procedure Heat I and II separately to about 60 C and slowly add I to II with thorough stirring to obtain a clear solution. Dissolve III in the hot solution IV to obtain a clear solution. Mix the cool solutions I/II, III/IV and V and adjust the ph value to Purge the solution with nitrogen for 10 min and fill into bottles under nitrogen. 3. Chemical stability (20 25 C; HPLC methods) (9 months) (12 months) Vitamin A 86 % 73 % Vitamin B1 88 % 83 % Vitamin B2 96 % 92 % Vitamin C 78 % 77 % 99

101 4.1.2 Complex formers Kollidon 25, Kollidon 30 One means of preparing an aqueous solution of a substance that is insoluble in water without using an organic solvent is to convert it into a soluble complex, e.g. with povidone. Kollidon 25 and Kollidon 30 can be used for this purpose in formulations for oral and topical administrations. The quantity of complexing agent required depends on the type of drug involved and its concentration. It also depends to some extent on the grade of povidone employed: The higher the molecular weight, the greater is the solubilizing effect. Important drugs with which this effect is used include antibiotics (e.g. amoxicillin, chloramphenicol and doxycycline), analgesics (e.g. acetaminophen and diclofenac) and particularly iodine which forms the well known povidoneiodine complex as water soluble disinfectant. Table 4.3 describes an oral solution of a diclofenac complex with Kollidon 30 as a typical example. Table 4.3: Diclofenac oral solution (1.5 %) 1. Formulation Diclofenac sodium Kollidon 30 Sucrose, crystalline Water 1.5 g 2.5 g 40.0 g 56.0 g 2. Procedure Dissolve diclofenac sodium in the aqueous solution of the auxiliaries. 3. Physical stability No crystallization had occurred after storage for 2 weeks at 6 C. A further example is the formulation an acetaminophen solution with Kollidon 25 given in Section

102 4.1.3 Poloxamers as solubilizers Lutrol F 68, Lutrol F 127 Poloxamers 188 and 407 (Lutrol F 68 and Lutrol F 127) are also used as solubilizers in oral and topical preparations. Lutrol F 68 is used primarily in oral preparations, while Lutrol F 127 is preferred for topical and buccal applications. Formulation No. 2 in Table 4.4 shows an application of Lutrol F 127 in a mouth wash, in which it serves mainly as a solubilizer, even though it is combined with ethanol and 1,2-propylene glycol as well. Table 4.4: alpha-bisabolol mouth wash solutions (0.2 % and 0.5 %) 1. Formulations No. 1 (= 0.2 %) No. 2 (= 0.5 %) I. Alpha-bisabolol, natural (BASF) 0.2 g 0.5 g Flavour q.s. q.s. Cremophor RH g Lutrol F g 1,2-Propylene glycol 10.0 g Ethanol 96 % 30.0 g II. Glycerol 5.0 g Saccharin sodium 0.1 g q.s. Preservative q.s. Water 92.2 g 54.5 g 2. Procedure Heat mixture I to about 60 C and add slowly the warm solution II (60 C). 3. Properties of the solutions Clear, colourless liquid with a low viscosity. 101

103 4.2 Solubilization for parenteral use Complex formers Kollidon 12 PF, Kollidon 17 PF As an increasing number of active ingredients are inadequately soluble in water, and organic solvents are hardly used any more, solubilizers are finding increasing use in injectables. As already described in Section 4.1, a number of products and mechanisms are suitable for this purpose. In the case of the low molecular weight povidone grades, Kollidon 12 PF and Kollidon 17 PF the principle involved is that of the formation of a soluble complex between the substance and povidone. Only povidone grades with a K-value of less than 18, which corresponds to an weight-average molecular weight of about 11,000, may be used for parenterals in Europe. The most important groups of active ingredients in human and veterinary ampoules for which these two grades of Kollidon have been used up to now to improve solubility are antibiotics, e.g. doxycycline, oxytetracycline and rifampicin as well as further anti-infectives. However, a number of other active substances e.g. certain analgesics and antiseptics can also be solubilized with povidone. Table 4.5 shows as an example of this application the composition of an aqueous oxytetracycline hydrochloride ampoule with Kollidon 17 PF for veterinary administration. Table 4.5: Composition of a commercial oxytetracycline injectable solution for veterinary administration Oxytetracycline-HCl Kollidon 17 PF Magnesium oxide Reducing agent e.g. sodium formaldehyde sulfoxylate Ethanolamine Water for injections 5.70 g g 0.46 g 0.50 g q.s. (ph) to 100 ml A further example of a formulation in which Kollidon 17 PF acts as a solubilizer is a retard ampoule for veterinary use in Section

104 4.2.2 Surfactants as parenteral solubilizers Solutol HS 15, Cremophor EL and Cremophor ELP As in the case with oral solutions (see Section 4.1), nonionic surfactants are also used as solubilizers in parenteral preparations. However, because of side effects such as the release of histamine, their suitability for use in an injectable formulation must be carefully checked. The only solubilizer that did not trigger the release of histamine in an animal trial was macrogol hydroxystearate 15 (Solutol HS 15), so that this product can be particularly recommended for parenterals. Though Cremophor EL is still relatively widely used particularly in veterinary formulations, it must now be declared on the package in Germany. Solutol HS 15 and Cremophor EL are frequently used to solubilize lipophilic substances, in particular vitamins and liponic acid. But they can also be used to solubilize other hydrophobic substances e.g. diazepam, ibuprofen, paclitaxel, propanidid etc. A special purified grade, Cremophor ELP is available for paclitaxel. Table 4.6 shows the formulation for a vitamin K1 ampoule as an example of an injection solution for human use. Table 4.6: Vitamin K1 (= phytomenadione) injectable solution (10 mg and 20 mg/ml) 1. Formulations No. 1 No. 2 Phytomenadione 1.0 g 2.0 g Solutol HS g 11.0 g Preservatives q.s q.s. Water for injections 93.0 g 87.0 g 2. Procedure Dissolve phytomenadione in Solutol HS 15 heated to about 60 C and slowly add the warm water. The solution can be sterilized by heating to 120 C or by filtering. 3. Properties of the solutions A clear colourless solution of low viscosity is obtained. 4. Physical stability (Formulation No. 1) After storage for 12 weeks at 20 C and 40 C, the heat-sterilized solution did not show any change in appearance. 103

105 Table 4.7 shows the formulation for one of the widely marketed veterinary ampoules with highly dosed vitamins A, D and E. This formulation gives a milky emulsion with very good physical and chemical stability. An indication of the bioavailability of the vitamins can be derived from results for a similar formulation in Section 4.7. Table 4.7: Vitamin A + Vitamin D3 + Vitamin E Aqueous Injectable Emulsion for Cattle (500,000 I.U. + 75,000 I.U mg/ml) 1. Formulation Vitamin A propionate 2.5 Mio I.U./g (BASF) Vitamin D3 40 Mio. I.U./g Vitamin E acetate (BASF) Butylhydroxytoluene Solutol HS 15 Benzyl alcohol Water for injections 22.0 g 0.2 g 5.5 g 0.5 g 15.0 g 1.0 g ad 100 ml 2. Procedure Mix the vitamins, Solutol HS 15, butylhydroxytoluene and benzyl alcoholat approx. 60 C, and then add the water (60 C) slowly and with vigorous stirring. After the ampoules have been heat-sterilized, they should be shaken briefly while still hot, to eliminate any separation of the phases that may have occurred. Sterilization can also be performed by membrane filtration under pressure. 3. Properties of the solution Appearance: milky, pale yellow emulsion. Viscosity: less than 20 mpa s 4. Physical stability (20 25 C, protected from light) No change in appearance in 2 years. 5. Chemical stability of vitamin A Room temperature: 9 % loss after 1 year, 16 % loss after 2 years. 6 C: About 10 % loss after 2 years Poloxamer 188 as parenteral solubilizer Lutrol F 68 Lutrol F 68 is the only poloxamer that is used in parenterals. As in oral and topical solutions, it can also serve as a parenteral solubilizer (see Section 4.1.3). 104

106 4.3 Thickeners High molecular povidone Kollidon 90 F Kollidon 90 F having a high weight-average molecular weight of more than 10 6 is used occasionally as a thickener in oral and topical solutions, even though rather higher concentrations are required than would be the case with some cellulose derivatives. Fig. 4.1 shows the variation in viscosity of aqueous solutions of Kollidon 90 F as a function of concentration. When Kollidon 90 F is used in aqueous solutions, it is recommended to add an antioxidant, e.g. 0.5 % cysteine, to stabilize the colour of the solution. mpa s , % Fig. 4.1: Dynamic viscosity of Kollidon 90 F in water (20 25 C) 105

107 4.3.2 Poloxamer 407 as thickener Lutrol F 127 The poloxamer Lutrol F 127 is also used as a thickener. The special feature of this product is that the thickening effect depends on the temperature, as is explained in detail in Section 6.2. Table 4.8 shows a formulation for an antiseptic solution with povidone-iodine as the active ingredient. This thermo-gelling antiseptic is liquid at room temperature, but when it is applied to the warm skin or mucous membranes, the Lutrol F 127 it contains causes its viscosity to increase to such an extent that it thickens to a gel with good adhesion. This feature is of particular interest in the treatment of burns. Table 4.8: Povidone-iodine thermo-gelling solution (10 %) 1. Formulation I. PVP-Iodine 30/06 (BASF) 10.0 g Sodium chloride 1.0 g II. Lutrol F g III. Sodium hydroxide solution, 1 molar 4.4 g IV. Water 69.6 g 2. Procedure Dissolve the solids (I) in water (IV), cool to about 6 C, dissolve Lutrol F 127 (II) in this and adjust the ph value with the sodium hydroxide solution (III) 3. Properties of the gelling solution Viscosity at room temperature viscous solution Viscosity on the skin (35 37 C) gel ph (20% in water) Stability (14 days, 52 C) ph (20% in water) 2.5 Loss of available iodine 9.7 % 106

108 4.4 Solvents Low molecular weight macrogols: Lutrol E grades The low-molecular-weight macrogols Lutrol E 300, Lutrol E 400 and Lutrol E 600 are used in liquid oral and topical preparations mainly as solvents. They are frequently used in syrups, drops, sprays, and topical solutions with the following active ingredients: Acetaminophen Clotrimazole, miconazole Isosorbide dinitrate Nifedipine Nitrazepam, diazepam Nitrofural. Low molecular weight liquid macrogols e.g. Lutrol E 300 and Lutro E 400 are occasionally used also in parenterals as solvents. In such cases, they are often combined with nonionic solubilizers or with 1,2-propylene glycol. The use of macrogols as solvents in injectables is not restricted to particular groups of active substances, though diclofenac sodium, etoposide, ibuprofen and nifedipine represent typical examples Propylene glycol 1,2-Propylene glycol is one of the few organic solvents that is still relatively widely used in pharmaceutical formulations. In contrast to ethanol, this also applies to preparations for oral administration. Examples of formulations of oral solutions with 1,2-propylene glycol are given in Tables 4.2, 4.4 and 4.9. Also in injectables for human use 1,2-propylene glycol is almost the only organic solvent that is still relatively frequently used. In such cases, it is occasionally used in combination with solubilizers or with liquid macrogols. As with the low molecular weight macrogols, its use is not restricted to any particular active substances, but the most important groups are probably analgesics e.g. diclofenac and piroxicam, corticoids, vitamins, and sedatives such as diazepam and digitalis glycosides. Typical formulations containing 1,2-propylene glycol for ampoules are given in Tables 4.10 (vitamin B complex) and 4.15 (closantel). 1,2-Propylene glycol in concentrations above 15% has a useful side effect in that it kills microbes. 107

109 4.5 Taste masking agents Kollidon 25, Kollidon 30 Povidone is capable of masking the unpleasant taste of some drugs to a certain extent, through the formation of a water-soluble complex. Kollidon 25 and Kollidon 30 are particularly suitable for this purpose in oral solutions. Typical examples of active ingredients, some of which are described in the literature, whose unpleasant taste can be masked with povidone, include guaifenesin, acetaminophen, trimethoprim and vitamin B formulations. This effect is demonstrated by the formulation in Table 4.9 for an acetaminophen solution, in which the bitter taste of the drug is almost completely masked by Kollidon 25. Table 4.9: Acetaminophen solution (5 % = 500 mg/10 g) 1. Formulation Acetaminophen (Merck) Sorbitol, crystalline Cyclamate sodium Strawberry flavour Kollidon 25 Glycerol 1,2-Propylene glycol Water 5.0 g 5.0 g 4.0 g 0.1 g 20.0 g 15.0 g 20.0 g 31.0 g 2. Procedure Dissolve first Kollidon 25 and then the other solid components in the solvent mixture of glycerol, propylene glycol and water. 3. Properties of the solution Clear solution of moderate viscosity with only a slightly bitter taste. 4. Physical stability The solution remained clear for more than 1 week at 6 C and for more than 3 months at 25 C and 40 C. The colour of the solution changed only slightly over 3 months at 25 C and 40 C. 5. Chemical stability (HPLC) No loss of acetaminophen was found after 3 months at 40 C. To avoid undesirable yellowing in aqueous solutions containing Kollidon 25 or Kollidon 30, it is recommended to add a stabilizer e.g. 0.5 % cysteine or 0.1 % sodium hydrogen sulphite. 108

110 4.6 Drug stabilizers in solutions Stabilizers of active ingredients in injectables Kollidon 17 PF Low molecular weight povidone, e.g. Kollidon 17 PF can be used to stabilize active ingredients in parenteral preparations. The mechanism of this effect has not been elucidated, but it may involve the formation of a complex. Concrete examples of the utilization of this stabilizing effect of Kollidon 17 PF are found above all in the field of vitamins and taurolidine. Table 4.10 gives the formulation for a vitamin B complex ampoule, in which cyanocobalamin is stabilized by Kollidon 17 PF. Table 4.10: Vitamin B complex injectable solution 1. Formulation I. Thiamine hydrochloride 1,100 mg Riboflavin phosphate sodium 660 mg Nicotinamide 4,400 mg Pyridoxine hydrochloride 440 mg Cyanocobalamin 880 µg EDTA, disodium salt 20 mg Propyl gallate 50 mg Kollidon 17 PF 10.0 g II. Parabens 160 mg Citric acid 2,270 mg Sodium hydroxide solution, 1 molar 21.6 ml Hydrochloric acid, 0.1 molar 72.0 ml 1,2-Propylene glycol 20.0 ml Water for injections 86.4 ml Total amount approx. 200 ml 2. Procedure Dissolve mixture I in the buffer solution II, purge with nitrogen for 5 min, filter through a 0.2 µm membrane filter and fill the clear yellow solution into ampoules of 2 ml under nitrogen. The ph is about Stability (20 25 C, dark) The following losses of vitamins were determined by HPLC: Vitamin 9 months 12 months B1 8 % 11 % B2 6 % 10 % Nicotinamide 0 % 0 % B6 9 % 9 % B12 13 % not tested Without Kollidon 17 PF the loss of vitamin B12 after 9 months was > 50 %. 109

111 4.6.2 Stabilizers of active ingredients in oral and topical solutions Kollidon 25, Kollidon 30 Kollidon 25 and Kollidon 30 also stabilize a number of active ingredients in aqueous oral, buccal or topical solutions. Typical active ingredients that can be mentioned and are described in the literature in this connection are: Interferon Iodine Isosorbide dinitrate Methylprednisolone Nitroglycerol Prostaglandin Taurolidine Theophylline Vitamins. 1,2-Propylene glycol 1,2-Propylene glycol is used mainly as a solvent, but it can also stabilize certain active ingredients. The best known example is vitamin C. Results can be found in the literature such as those in Fig. 4.2 which show that 1,2-propylene glycol has a very strong positive effect on the stability of ascorbic acid solutions. Without 1,2-propylene glycol, the vitamin loss after 240 days is 81 % and with 50 % 1,2-propylene glycol it is less than 10 % after the same storage time. Vitamin content, % Water Propylene glycol + Water 1+1 Propylene glycol Fig. 4.2 : Influence of the solvent on the stability of ascorbic acid solutions (240 days, 22 C) 110

112 The good stability of the vitamins B1 to B6 in the vitamin B complex ampoule in Table 4.10 is most likely also due to the 1,2-propylene glycol content in the formulation D,L-alpha-Tocopherol as antioxidant The antioxidant D,L-alpha-tocopherol is particularly suitable for stabilizing lipophilic substances in oily solutions and aqueous microemulsions (= solubilizates). Vitamins A and D, and the essential fatty acids are the main substances concerned here. The quantities of alpha-tocopherol required are rather higher than those of other antioxidants such as butylhydroxytoluene, but alpha-tocopherol is also approved worldwide for use in food. A typical example of a vitamin formulation with alpha-tocopherol as an antioxidant is given in Table 4.11 for vitamin A + E drops. Table 4.11: Vitamin A + Vitamin E drops (25,000 I.U mg/ml) 1. Formulation I. Vitamin A palmitate 1.7 Mio. I.U./g. (BASF) 1.5 g Vitamin E acetate (BASF) 5.0 g Cremophor RH g DL-alpha-Tocopherol (BASF) 1.0 g II. Preservative q.s. Water 71.5 g 2. Procedure Mix the vitamins with Cremophor RH 40 (and DL-alpha-tocopherol) at 60 C and then add solution II (at 37 C) slowly, with stirring. 3. Properties of the solutions Clear, yellow, viscous liquids. 111

113 4.7 Enhancers of bioavailability in injectables Solutol HS 15, Cremophor EL The use of nonionic solubilizers as a means of improving the bioavailability of active ingredients in injectables is of interest above all for lipophilic substances such as vitamins. Fig. 4.3 compares the bioavailability of an aqueous emulsion formulation similar to that in Table 4.7 with that of other commercially available formulations based on vegetable oils or organic solvents. 70 Vitamin A, found in the liver [%] Aqueous emulsion Organic solution Oily solution Fig. 4.3: Bioavailability of Vitamin A in injectables after 7 days (intramuscular application in broilers) 112

114 4.8 Film formers for topical aerosols Kollicoat IR, Kollidon VA 64 The two film formers Kollicoat IR and Kollidon VA 64 described in the Section 1.6 for soluble tablet coatings are also suitable for topical aerosols. A typical formulation of an antiseptic wound spray with Kollicoat IR is given in Table This formulation was developed for the use as a manual pump spray but it would also be possible to add propellents and fill it in usefull aerosol cans. Table 4.12: Antiseptic povidone-iodine wound spray 1. Formulation I. PVP-Iodine 30/06 (BASF) 10 g Kollicoat IR 5 g II. Ethanol 96 % 43 g Water 42 g 2. Procedure Dissolve the components I in the mixture II and fill in flasks for manual pump sprays. 3. Properties of the solutions Aspect Viscosity Drying on the skin Chemical stability (1 year, rt) brown, clear solution low fast, it forms a washable film less than 10 % loss of iodine The main application field of Kollidon VA 64 in aerosols actually is a topical veterinary spray of fipronil against parasits of dogs and cats. 113

115 4.9 Lyophilization agents Kollidon 12PF, Kollidon 17PF, Kollidon 25, Kollidon 30 Different grades of povidone (Kollidon 12PF and Kollidon 17PF for injectables and Kollidon 25 and Kollidon 30 for oral and topical preparations) can also be used as lyophilizing agents. They act as a binder in the same way as mannitol, holding the powder together during the freeze-drying process and preventing splashing, and also as a solubilizer or suspension stabilizer that facilitates reconstitution with the solvent prior to use by the patient. Table 4.13 shows the formulation for an amoxicillin lyophilizate with Kollidon 12 PF, taken from an old patent granted in Table 4.13: Amoxicillin lyophylizate for injection (250 mg) 1. Formulation Amoxicillin sodium Kollidon 12 PF Water for injections 6.25 g 7.50 g ad ml 2. Procedure Dissolve the active ingredient in the well stirred solution of Kollidon 12 PF in water, freeze-dry, then fill 500-mg-portions of the dry lyophilizate into ampoules. 3. Administration Prior to administration, mix the dry content of an ampoule with 1.9 ml of water for injections to give a clear injection solution. 114

116 4.10 Sustained-release agents in veterinary parenteral solutions Soluphor P There are very few sustained-release agents for parenteral use as almost all polymers are either degraded too rapidly, or eliminated too soon if they have a low molecular weight, or are eliminated much too slowly if they have a high molecular weight. In the field of veterinary medicine, 2-pyrrolidone (Soluphor P) has been used successfully for many years to achieve this effect in intramuscular injectable solutions, though at %, the concentration required is relatively high. Table 4.14 shows, as a typical example, a formulation for an oxytetracycline sustained-release ampoule, taken from an old patent from Table 4.14: Oxytetracycline sustained-release injectable solution for veterinary i.m. administration (2.2 g/10 ml) 1. Formulation Oxytetracycline Magnesium oxide Soluphor P Kollidon 17 PF Sodium formaldehyde sulfoxylate 2-Aminoethanol Water for injections g 1.92 g g 5.00 g 0.44 g 3.84 g q.s. ad ml 2. Procedure Mix the water and the Soluphor P, and dissolve the Kollidon 17 PF in the mixture. Heat the solution to 75 C. Add the sodium formaldehyde sulfoxylate and stir until dissolved. After the magnesium oxide has been suspended, slowly stir in the oxytetracycline until a clear solution is obtained. After the solution has cooled, adjust to ph 8.5 with aminoethanol. 3. Remarks High quality oxytetracycline and a complete absence of oxygen during the manufacture and packaging of the solution are essential to obtain a solution with acceptable chemical stability. The reducing agent selected e.g. sodium formaldehyde sulfoxylate must meet the regulations of the country in which it is to be used. 115

117 4.11 Reduction of toxicity of active ingredients Kollidon 12 PF, Kollidon 17 PF The reduction of the local toxicity of some active ingredients by complexation with povidone is utilized not only in topical solutions with iodine, but also in parenterals. The best-known example of such a drug is oxytetracycline, whose local irritating effect at the point of injection can be reduced by adding Kollidon 17 PF. Another example is the closantel veterinary ampoule described in Table 4.15 in which the addition of Kollidon 17 PF has been demonstrated to reduce the size of the oedema that appears around the point of injection by 80 %. Table 4.15: Closantel veterinary injectable solution (12 20 g/100 ml) 1. Formulation I. Closantel g II. Kollidon 12 PF or Kollidon 17 PF g Sodium hydroxide, 50 % in water g 1,2-Propylene glycol approx. 60 g III. Sodium hydrogen sulfite g Water for injections approx. 20 g 2. Procedure Dissolve Closantel in solution II and add solution III. Sterilize by heating to 120 C for 20 min. 3. Properties of the solution Clear yellow solution 4. Remarks The function of Kollidon 12 PF or Kollidon 17 PF is to greatly reduce the local side-effects (e.g. formation of oedemas) and to increase the retention time in the tissue. 116

118 117

119 118

120 5. Suspensions (Ready-to-use suspensions, dry syrups, instant drink granules) 5.1 Sedimentation inhibitors for oral and topical use Micronized crospovidone Kollidon CL-M One of the greatest problems in the development of formulations for suspensions is the prevention of sedimentation over the necessary period. Thickeners such as cellulose derivatives are traditionally used as sedimentation inhibitors to increase the relative sediment volume. However, these substances have the major disadvantage that by increasing the viscosity, they make it more difficult to shake up the preparation. An alternative that gives the same effect, but without increasing the viscosity, is therefore preferable. Kollidon CL-M provides this alternative as a result of its special physical properties such as its low bulk density, its small particle size, its relatively high specific surface area and the low viscosity of aqueous suspension of the substance. Furthermore, Kollidon CL-M does not reduce the zeta potential of the active substance particles and sterically holds them apart. 120 Viscosity, mpa s Kollidon CL-M, g/100 ml Fig. 5.1: Dynamic viscosity of amoxicillin dry syrup suspensions with different amounts of Kollidon CL-M 119

121 As can be seen from Fig. 5.1, oral amoxicillin suspensions with concentrations of Kollidon CL-M up to 10 % can be prepared without exceeding a viscosity of 80 mpa s. As the usual concentrations cover a range of 5 to 8 % Kollidon CL-M (6 % in the case of the amoxicillin dry syrup), the change in viscosity is hardly visible. The suspensions were prepared by shaking amoxicillin dry syrups (amoxicillin trihydrate 5 g, sodium citrate 5 g, citric acid 2 g, sodium gluconate 5 g, sorbitol 40 g, Kollidon CL-M 0 10 g, flavours 2 g, saccharin sodium 0.4 g) with the amount of water to fill up to the volume of 100 ml. A other typical formulation for a low-viscosity oral suspension is the ibuprofen suspension given in Table 5.1. Most of the suspension formulations containing Kollidon CL-M as a sedimentation inhibitor, such as that in Table 5.1, contain a series of further excipients that also help to stabilize the suspension. These include Kollidon 90 F, sucrose and sorbitol as well as an ionic component such as sodium citrate, that also increases the sediment volume. Table 5.1: Ibuprofen oral suspension (4 % = 200 mg/5 ml) 1. Formulation Ibuprofen (BASF) Kollidon 90 F Sodium citrate Sucrose Kollidon CL-M Water 4.0 g 2.0 g 2.0 g 25.0 g 8.0 g ad 100 ml 2. Procedure Dissolve sucrose, Kollidon 90 F and sodium citrate in about 40 ml of water, suspend Kollidon CL-M and ibuprofen in this solution by stirring and add the rest of the water. 3. Physical properties of the suspension After 1 day After 1 month (RT) Color Milky white Milky white Relative sediment volume 100 % 94 % Redispersibility Not necessary Very easy Viscosity Low Low Aspect Homogeneous Homogeneous The effect on the relative sediment volume after a period of 2 weeks of varying the concentration of Kollidon CL-M in the ibuprofen suspension described in Table 5.1 is shown in Fig The small sedimentation obtained with the use of 8 % of Kollidon CL-M can still be regarded as good, as the low viscosity of the formulation makes redispersion easy. 120

122 Relative sediment volume, % (14 days) Kollidon CL-M, % Fig. 5.2: Influence of the amount of Kollidon CL-M on the sedimentation of an ibuprofen suspension (Formulation see Table 5.1) Table 5.2 contains a formulation for acetaminophen instant drink granules as an example of a suspension that is prepared as required by the patient himself. These granules for suspension in water also contain sodium citrate and citric acid as further sedimentation inhibitors. As further benefits, Kollidon CL-M completely masks the bitter taste of the active substance and stabilizes its content in the granules. Table 5.2: Acetaminophen instant drink granules (250 mg or 500 mg) 1. Formulation I. Acetaminophen, fine powder 50 g Sorbitol Instant (Merck) 130 g Kollidon CL-M 50 g Aspartame 7 g Orange aroma 5 g Strawberry aroma 5 g Sodium citrate 3 g Citric acid 3 g II. Kollidon 90 F 8 g Ethanol 96 % 50 g 2. Procedure (wet granulation) Granulate mixture I with solution II, and pass through a 0.8 mm sieve. Fill 1.3 g or 2.6 g of the free flowing granules in sachets corresponding to 250 mg or 500 mg of acetaminophen. 3. Administration form Suspend the content of one sachet in a glass of water. The milky suspension has a sweet and fruity taste. 121

123 The use of Kollidon CL-M as a suspension stabilizer is not limited to aqueous systems. It also stabilizes suspensions in organic solvents such as paraffin. Simethicone oil can also be incorporated as active ingredient in homo-geneous instant drink granules with the aid of Kollidon CL-M (see Table 5.9) Povidone as sedimentation inhibitor for oral and topical use Kollidon 90 F, Kollidon 30 Like Kollidon CL-M, soluble polymers can also act as sedimentation inhibitors, since, above a certain molecular weight, they do not alter the zeta potential of the active ingredient particles. Of the range of soluble povidones, Kollidon 90 F and Kollidon 30 should be mentioned for this application in oral and topical suspensions. Fig. 5.3 shows the effect of Kollidon 90 F on the relative sediment volume of a oral carbamazepine suspension (Formulation: carbamazepine 2 %, Kollidon CL-M 7 %, 1,2-propylene glycol 10 %, water %). It can be seen clearly that even small quantities of Kollidon 90 F are effective in reducing sedimentation. 100 Relative sediment volume after 2 days % Kollidon 90 F Fig. 5.3: Influence of Kollidon 90 F on the sedimention of a carbamazepine suspension In some formulations, Kollidon 30 has proved superior to Kollidon 90 F. This is not only because of the lower viscosity of its solutions. The sediment formed by the oral aciclovir suspension in Table 5.3 with Kollidon 90 F was too compact. However, 3 % Kollidon 30 was determined as the optimum for minimum sedimentation and easy redispersibility in combination with Kollidon CL-M. 122

124 Table 5.3: Aciclovir oral suspension (2 % = 200 mg/10 ml) 1. Formulation Aciclovir Kollidon CL-M Kollidon 30 Sorbitol, crystalline Citric acid Preservative Water 2.0 g 6.0 g 3.0 g 28.0 g 0.5 g q.s g 2. Procedure Suspend aciclovir and Kollidon CL-M in the solution of the other components with vigorous stirring 3. Properties of the solution Color white Relative sediment volume after 14 days 96 % Redispersibility after 14 days easy Apart from their use in ready-to-use suspensions, instant drink granules and dry syrups, Kollidon 25 and Kollidon 30 can also be used to stabilize the pigment and spray suspensions that are used for coatings. Typical examples of this application are given in Sections 1.7 and

125 5.1.3 Poloxamers as sedimentation inhibitors for oral and topical use Lutrol F 68, Lutrol F 127 The two poloxamers 188 and 407 (= Lutrol F 68 and Lutrol F 127) can also influence the sediment volume of a suspension. Table 5.4 gives a formulation for albendazole dry syrup. The suspension prepared by the patient by adding water contains 1 % Lutrol F 68. Table 5.4: Albendazole dry syrup (200 mg/10 ml) 1. Formulation I. Albendazole 4 g Citric acid 3 g Sodium citrate 3 g Sorbitol, crystalline 88 g II. Ethanol 96 % 22 g Lutrol F 68 2 g 2. Procedure (wet granulation) Granulate mixture I with solution II, pass through a 0.8 mm screen, dry and sieve again. Fill 50 g of the granules into a 100-ml flask. 3. Administration form Fill the flask containing 50 g of granules with water to the 100-ml mark. The suspension obtained has no bitter taste. A further formulation with Lutrol F 68 is shown in Table 5.5 in the form of aceclofenac instant granules. Lutrol F 127 is recommended more for use in topical suspensions. The use of poloxamers in suspensions is not restricted to aqueous systems. They can also be used to stabilize oily suspensions e.g. of antibiotics in vegetable oils. 124

126 5.1.4 Surfactants as sedimentation inhibitors for oral and topical use Cremophor RH 40, Cremophor EL Surfactants such as macrogolglycerol hydroxystearate 40 (= Cremophor RH 40) increase the wettability of the solid particles in a suspension and reduce the surface tension of the continuous phase. This prevents, among other things, the flotation of the particles and reduces aggregate formation, which increases the sediment volume. Often even very small quantities of Cremophor RH 40 suffice to achieve a stabilizing effect in a suspension. For example, calculation shows that the suspension prepared by the patient in a glass of water of 3.9 g of the aceclofenac instant granules described in Table 5.5 contains only % Cremophor RH 40. Since magrogolglycerol ricinoleate (= Cremophor EL) has a bitter taste like polysorbate it is less suitable for oral dosage forms but usefull for topical forms like Cremophor RH 40 too. Table 5.5: Aceclofenac instant granules (50 mg) 1. Formulation (granules) I. Aceclofenac 1.3 g Orange flavour 4.3 g Sorbitol, crystalline 85.6 g II. Lutrol F g Cremophor RH g Water about 50 g 2. Procedure (wet granulation) Granulate mixture I with solution II, pass through a 0.8 mm screen, dry and sieve again. Fill 3.9 g in sachets corresponding to 50 mg aceclofenac. 3. Properties of the granules Free flowing, water dispersing granules having almost no bitter taste. The ability of Cremophor RH 40 to improve the wettability of solid particles in a suspension is also used in suspensions for the sugar-coating and for film-coating of tablets. 125

127 5.2 Redispersing agents for oral and topical use Micronized crospovidone Kollidon CL-M Kollidon CL-M not only improves the physical stability of a suspension by slowing sedimentation and increasing the sediment volume, it also improves its redispersibility through steric separation of the drug particles and above all through its low viscosity. A clear distinction between the two functions of the low bulk density product Kollidon CL-M cannot be recognized. Tables , 5.6 and contain typical examples of formulations in which Kollidon CL-M is used also as a redispersing agent Povidone Kollidon 90 F, Kollidon 30 Povidone (e.g. Kollidon 90 F or Kollidon 30) dissolves in the continuous phase of a suspension as a polymer, separating the drug particles without lowering their zeta potential. Just as with Kollidon CL-M, these two products can act as redispersing agents by increasing the sediment volume. Table 5.3 shows a formulation in which Kollidon 30 is used for this purpose in an aciclovir suspension. Kollidon 90 F has the same function in the formulation for the magaldrate suspension shown in Table 5.6. Because of possible problems with microbiological stability, it may be desirable to modify the formulation to obtain an instant syrup. If the concentration of Kollidon 90 F in the antacid suspension in Table 5.6 is varied, a significant change in the redispersibility of the suspension can be observed. Fig. 5.4 illustrates this effect, showing the number of inversions of the bottle required to obtain a homogeneous suspension, each 180 motion taking 2 seconds. It can be seen clearly that 3 % Kollidon 90 F is the optimum concentration for ready redispersibility. 126

128 Table 5.6: Magaldrate suspension (10 %) 1. Formulation Magaldrate USP Kollidon CL-M Sucrose Kollidon 90 F Orange flavour Coconut flavour Banana flavour Saccharin sodium Water 10.0 g 8.0 g 15.0 g 3.0 g 1.0 g 0.05 g 0.08 g 0.02 g ad 100 ml 2. Procedure Dissolve and suspend all the solids in water under aseptic conditions. 3. Properties of the suspension No sedimentation after 24 hours Very easy to redisperse after more than 2 weeks 25 Number of shakings needed for reconstitution after 1 week Kollidon 90 F, % Fig. 5.4: Influence of Kollidon 90 F on the redispersibility of a magaldrate suspension (Formulation see Table 5.6) 127

129 5.3 Sedimentation inhibitors and redispersing agents for injectables Low molecular povidone Kollidon 12 PF or Kollidon 17 PF In the same way as Kollidon 30 and Kollidon 90 F can be used in oral suspensions (Section 5.1.2), the two low molecular weight povidone grades, Kollidon 12 PF and Kollidon 17 PF are suitable for use in parenteral suspensions. Because of their low viscosity, they are usefull in injectables as sedimentation inhibitors and redispersing agents. Typical examples of commercialized parenteral drug formulations in which low molecular weight povidone is used as a suspension stabilizer include benzylpenicillin, fluspirilen, methylprednisolon and streptomycin preparations. Table 5.7 shows a formulation for a parenteral antibiotic suspension with Kollidon 12 PF. Table 5.7: Benzylpenicillin + dihydrostreptomycin injectable suspension (200,000 units mg/ml) 1. Formulation I. Procaine benzylpenicillin 20.0 g Dihydrostreptomycin sulfate 20.0 g II. Kollidon 12 PF 0.5 g Carboxymethyl cellulose sodium 0.5 g Sodium citrate 0.6 g Parabens q.s. Water for injections ad 100 ml 2. Procedure Prepare solution II, suspend the components I in the well stirred solution II and pass through a colloid mill. 3. Properties A white homogeneous suspension is obtained Surfactants as sedimentation inhibitors and redispersing agents for injectables Solutol HS 15 Just as Cremophor RH 40 can be recommended as a sedimentation inhibitor and redispersing agent in oral suspensions (Section 5.1.4), macrogol hydroxystearate 15 (= Solutol HS 15) is suitable for use in parenteral suspensions for the same purpose. It gives solutions of low viscosity in water, even at high concentrations of up to 30 %. 128

130 5.4 Crystallization inhibitors and solubilizers in suspensions Solvent 1,2-Propylene glycol In some suspensions, it is important to ensure that the relatively small proportion of dissolved active ingredient does not crystallize out, as this could change the physical properties of the suspension and its stability. 1,2-Propylene glycol is a solvent that can prevent such crystallization. The formulation for a carbamazepine suspension in Table 5.8 is a typical example. In the presence of water, the small proportion of dissolved carbamazepine has a tendency to change into the hydrate which, however, is less soluble and can therefore crystallize out as needles. The addition of 20 % 1,2-propylene glycol prevents this phenomenon. Table 5.8: Carbamazepine oral suspension (2 %) 1. Formulation Carbamazepine (Flavine) 1,2-Propylene glycol Kollidon 90 F Saccharin sodium Sodium citrate Sorbitol, crystalline Kollidon CL-M Water 2.0 g 20.0 g 3.0 g 0.1 g 1.0 g 25.0 g 7.0 g 41.9 g 2. Procedure Stir the mixture of carbamazepine and 1,2-propylene glycol for at least 2 hours, add Kollidon 90 F, saccharin, sodium citrate and the water and stir again until these components are dissolved. Dissolve sorbitol in this mixture and add Kollidon CL-M to the well stirred suspension to obtain a homogeneous suspension. 3. Properties of the suspension After 1 day After 1 month (RT) Colour Milky white Milky white Relative sedimentation volume 100 % 98 % Redispersibility Not needed Very easy Structure of the sediment Very fine particles, Very fine particles, no crystals no crystals Viscosity Very low Very low 129

131 5.4.2 Surfactants as solubilizers in suspensions Cremophor RH 40, Cremophor EL The solubilizers macrogolglycerol ricinoleate 35, macrogolglycerol hydroxystearate 40 and macrogol hydroxystearate 15 (Cremophor EL and Cremophor RH40 for oral use and Solutol HS15 for injectables) solubilize the active ingredients not only in solutions but also in suspensions. Here, they act in a similar manner to 1,2-propylene glycol in preventing the dissolved part of the active ingredient from recrystallizing, stabilizing the physical properties of the suspension. The solubilizing effect of Cremophor RH 40 is also used in oral and topical suspensions for incorporating lipophilic drugs, fragrances and flavours (e.g. menthol in Table 5.10). The formulation for simethicone instant granules in Table 5.9 is a typical example for the solubilization and emulsification of an active ingredient. In this case, a milk-like combination of emulsion and suspension is obtained as soon as the patient adds the granules to water. Table 5.9: Simethicone instant granules (60 mg and 120 mg) 1. Formulation I. Simethicone (Abil 200, Goldschmidt) 10.0 g Cremophor RH g II. Kollidon VA g Ethanol 40.0 g III. Sorbitol, crystalline (Merck) 50.0 g Fructose (Merck) 50.0 g Kollidon CL-M 50.0 g Orange flavour (Dragoco) 0.5 g 2. Procedure Introduce solution II into the mixture I, granulate the powder mixture III with the well stirred mixture I/II, dry and pass through a 1 mm sieve. Fill 1 g or 2 g portions into sachets. 3. Properties of the granules Free-flowing white granules; 98 % coarser than 50 µm; Easily dispersing in water; no physical separation within 30 min. 4. Administration Disperse the contents of one sachet (1 g = 60 mg simethicone or 2 g = 120 mg simethicone) in about 100 ml of drinking water. 130

132 5.4.3 Macrogols Lutrol E 400, Lutrol E 600 Macrogols of low molecular weight are also used in parenteral suspensions, and particularly in crystal suspensions. This is of interest for drugs such as corticoids, e.g. methylprednisolone or triamcinolone and hormone derivatives, e.g. medroxyprogesterone. 131

133 5.5 Taste masking agents in suspensions Micronized crospovidone Kollidon CL-M Kollidon CL-M not only improves the physical stability and redispersibility of oral suspensions, it is also able to mask partly or completely the unpleasant taste of a series of active ingredients. The mechanism of this effect is unknown, but it has been found with most formulations that a relatively large quantity of Kollidon CL-M is required in relation to the drug. In lowdose preparations, this presents no problems, but in high dose preparations such as acetaminophen chewable tablets, it can be costly, and difficult to obtain a workable formulation. Kollidon CL-M has proved particularly suitable for taste masking in instant drink granules and dry syrups. Typical examples of this application are the formulations for acetaminophen instant granules and azithromycin dry syrup in Tables 5.2 and 5.10 Table 5.10: Azithromycin dry syrup (5 % = 500 mg/10 ml) 1. Formulation I. Azithromycin dihydrate 5.0 g Sodium citrate 5.0 g Citric acid 2.0 g Sucrose 60.0 g Sodium cyclamate 0.5 g Kollidon CL-M 9.0 g II. Ethanol 9.0 g Menthol, crystalline 0.5 g Cremophor RH g 2. Procedure (wet granulation) Mixture I is granulated with solution II. The granules obtained are passed through a 1.0 mm sieve and dried at room temperature. Fill 83 g of the granules into a 100 ml flask. 3. Administration form Shake 83 g of the granules with drinking water and fill the flask to the 100 ml mark. The suspension obtained has practically no bitter taste. 132

134 5.5.2 Poloxamer for taste masking Lutrol F 68 Poloxamer 188 (= Lutrol F 68) not only acts to prevent sedimentation in oral suspensions, it can also partly or completely mask the unpleasant taste of a number of drugs. The formulations for an albendazole dry syrup (Table 5.4) and aceclofenac instant granules (Table 5.5) are typical examples of this effect. 133

135 5.6 Stabilizer of active ingredients in instant granules and dry syrups Kollidon CL-M Reducing the susceptibility of active ingredients to oxidation and hydrolysis contributes greatly to improving the stability of a preparation. Owing to its enormous water-binding capacity and high surface, micronized crospovidone Kollidon CL-M acts as a strong desiccant in solid dosage forms such as instant granules and dry syrups. As a result, it is able to stabilize drugs that are susceptible to hydrolysis, and prevent chemical reactions such as interactions between vitamins, and their oxidation. Table 5.11: Multivitamin instant granules (2 4 RDA of vitamins) 1. Formulation I. Vitamin A + D powder 250, ,000 I.U./g 200 g CWD (BASF) Thiamine mononitrate 26 g Riboflavin 33 g Nicotinamide 110 g Pyridoxine hydrochloride 22 g Calcium D-pantothenate 150 g Cyanocobalamin gelatin coated 0.1 % 66 g Ascorbic acid powder 1,150 g Vitamin E acetate dry powder SD 50 (BASF) 210 g Sucrose, finely ground 20,000 g Kollidon CL-M 5,000 g Orange flavour 1,000 g II. Kollidon VA 64 2,000 g Ethanol or isopropanol approx. 7 l 2. Procedure (wet granulation, fluidized bed) Pass mixture through a 0.8 mm sieve and granulate with solution II. Fill 6 12 g of the free flowing granules into sachets. 3. Administration Suspend 6 12 g (= 1 sachet) in a glass of water corresponding to 2 4 RDA of vitamins. The uniform, yellow suspension obtained shows no sedimentation over a period of some hours. 4. Chemical stability After storage of the granules for 1 year at room temperature, the following vitamin contents were measured by HPLC: Vitamin C: 94 % All other vitamins: > 95 % 134

136 The multivitamin instant granules in Table 5.11 represent an example of this application. With the exception of vitamin C, none of the vitamins showed any statistical loss after storage of the granules for 1 year at room temperature. Even the loss of vitamin C was only 9 %. When the same granules were produced without Kollidon CL-M, the losses of some vitamins were considerable. The acetaminophen instant granules described in Table 5.2 are a further example of this application of Kollidon CL-M. In an accelerated storage test at 60 C over 2 months, the granules were found to have not lost any of their potency at all. 135

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140 6 Semisolid dosage forms (Gels, creams, suppositories, transdermal systems) 6.1 Emulsifiers Cremophor A 6, Cremophor A 25 The two macrogol cetostearyl ethers Cremophor A 6 and Cremophor A 25 are excellent emulsifiers for the manufacture of pharmaceutical and cosmetic creams. Even relatively small concentrations of these two Cremophor A grades suffice to form a stable emulsion. The best results are obtained by combining the two products, as has been done in the formulation for a cream base shown in Table 6.1. This formulation is suitable for a wide range of active ingredients; they are dissolved in 1,2-propylene glycol prior to incorporation in the cream base. Typical examples of substances that have been tested in this formulation are betamethasone, bifonazole, clotrimazole, hydrocortisone and miconazole. Table 6.1: Cream base for different active ingredients 1. Formulation I. Cetostearyl alcohol 7.0 g Cremophor A g Cremophor A g Liquid paraffin 12.0 g Parabens 0.2 g II. Water g III. 1,2-Propylene glycol 8.0 g Active ingredient g 2. Procedure Heat mixture I and the water II separately to about 80 C. Add the water II to the solution of mixture I with vigorous stirring. Heat III until the active ingredient has dissolved, mix with I/II and continue to stir while cooling to room temperature. 3. Properties White cream 4. Physical stability No change in appearance was observed after 6 weeks at 45 C. 139

141 6.2 Poloxamer as gel forming agent Lutrol F 127 Poloxamer 407 (= Lutrol F 127) is a gel former with special properties. Firstly, the gels it gives are stable over a relatively wide ph range of 4 8, and secondly, the gel formation is thermoreversible. However, it must be mentioned that the concentrations required are quite high, and that the gels obtained are slightly tacky. The thermoreversibility of the gel is shown in Fig It has a gel structure between 25 C and C, and is liquid outside this range Viscosity, mpa s 16% 22% 18% 20% 20% 18% 22% 16% Temperature, C Fig. 6.1: Viscosity of gels of Lutrol F 127 in water (Brookfield viscosimeter, rotation 250 rpm) The curves in Fig. 6.1 show that a concentration of at least 18 % Lutrol F 127 is required in aqueous solutions without other additives to obtain a gel at room temperature. There are various means of modifying these curves. The ph has only a minor effect on the position of the curves within the recommended limits of ph 4 7. However, the concentration of a number of ions has a definite effect. The addition of 0.9 % sodium or potassium chloride extends the curves to the right by some 10 C, while higher concentrations, e.g. 5 % of the same ions shifts the whole curves to the left by C. A formulation that takes advantage of this thermoreversibility is the thermogelling PVP-iodine solution presented in Section that turns into a gel when it is applied to the skin. The formulation for a topical ibuprofen gel that has the desired gel structure even at room temperature is given in Table 6.2. Further formulations with Lutrol F 127 as a gel former in transparent gels and in a gel cream are given in Tables 6.3 and

142 Table 6.2: Ibuprofen gel (5 %) 1. Formulation I. Ibuprofen 5 g Ethanol 96 % 10 g 1,2-Propylene glycol 10 g II. Lutrol F g III. Isopropyl myristate 1 g Preservative q.s. Water 59 g 2. Procedure Dissolve II in solution III at 70 C under vacuum, cool to 40 C and add solution I. 3. Properties of the gel A colourless clear gel is obtained. 4. Remark The function of the isopropyl myristate is to reduce the tack. 141

143 6.3 Solubilizers in gels, creams and suppositories Cremophor RH 40 and Lutrol F grades Nonionic surfactants are also required in semisolid dosage forms to solubilize the active ingredient. This applies in particular to transparent gels, but is also important for creams in which the active principle must be in a dissolved or solubilized form, and not in crystalline form, for good absorption. Because of its weak odour and good solubilizing power, macrogolglycerol hydroxystearate 40 (= Cremophor RH 40) is particularly suitable for this purpose. Table 6.3 shows the formulation for a mouth gel in which Cremophor RH 40 solubilizes the insoluble active ingredient miconazole. Table 6.3: Miconazole mouth gel (2%) 1. Formulation I. Miconazole nitrate (Sigma) 2.0 g Orange flavour 0.1 g II. Lutrol F g Cremophor RH g 1,2-Propylene glycol 10.0 g III. Kollidon 90 F 5.0 g Saccharin sodium 0.3 g Water 52.6 g 2. Procedure Dissolve I in the melted mixture II. Heat solution III to 90 C and mix slowly with I/II. Once the air bubbles have escaped, allow to cool to room temperature. 3. Properties of the gel A clear, colourless, soft gel was obtained, with an orange flavour and a slightly bitter aftertaste. However, solubilizers are also used in suppositories to homogeneously dissolve lipophilic active substances in a hydrophilic matrix, or to improve their absorption. Table 6.4 shows an example of the use of Cremophor RH40 in vitamin A suppositories. 142

144 Table 6.4: Vitamin A suppositories (150,000 I.U.) 1. Formulation Vitamin A palmitate 1.7 Mio I.U./g (BASF) Vitamin A palmitate 1.7 Mio I.U./g (BASF) Butylhydroxytoluene Cremophor RH 40 Macrogol 1500 Macrogol g 9 g 1 g 40 g 80 g 50 g 2. Procedure Dissolve butylhydroxytoluene in the warm vitamin A, add Cremophor RH 40 and mix with the molten macrogols. Fill into moulds of suppositories to obtain the weight of 2 g. 3. Properties of the gel Weight 2.0 g Colour Homogeneously yellow Drop point 54 C Macrogol g Disintegration in water 22 min (emulsion) Poloxamers 188 and 407 (Lutrol F 68 and Lutrol F 127) can also be used as solubilizers in semisolid dosage forms just as in oral forms (see also Section 4.1.3). 143

145 6.4 Absorption enhancers in semisolid dosage forms Complex formers Kollidon 25, Kollidon 30, Kollidon CL-M In semisolid dosage forms such as suppositories, creams and transdermal systems, medium molecular weight povidone (Kollidon 25, Kollidon 30) can be used to accelerate absorption and bioavailability. Fig. 6.2 shows the effect of povidone on the release of phenobarbital from suppositories in rabbits. In the first 2 hours, the blood level increases by a factor of 3 as a result of the use of a coprecipitate of phenobarbital and povidone, and even after 6 hours, the blood level is still twice as high as without povidone. 25 Blood level, mg/µl Without povidone 5 Copreciptate with povidone (1+3) Hours Fig. 6.2: Absorption of phenobarbital from suppositories in rabbits The effect that povidone can have in a formulation on the percutaneous absorption of hydrocortisone acetate is demonstrated in Fig Here, the absorption through human skin was increased several times, particularly after 60 min, and particularly if a coprecipitate of the drug and povidone was used. 144

146 Relative vasoconstriction effect after 30 min after 60 min 0 Without povidone With povidone, phys. mixture 1+2 With povidone, coprecipitate 1+2 Fig. 6.3: Percutaneous effect of hydrocortisone acetate on the human skin Just as the use of povidone (e.g. Kollidon 30) in traditional topical dosage forms e.g. creams to accelerate percutaneous absorption, its use for the same purpose in transdermal systems is also possible. Descriptions of its use with a number of drugs, for example bromhexine, captopril, diclofenac, flurbiprofen, isosorbide dinitrate, nitroglycerin and propranolol can be found in the pharmaceutical literature. The micronized grade of crospovidone, Kollidon CL-M can also be used to achieve a similar absorption-accelerating effect in transdermal systems. The effect derives from the formation of a complex with the active ingredient like in the case of povidone, as already described for oral preparations in Sections and A typical example of a drug to which this effect is applied is estradiol. 145

147 6.4.2 Solvent as absorption enhancer 1,2-Propylene glycol The solvent 1,2-propylene glycol has also the function as a percutaneous absorption enhancer in semisolid dosage forms such as gels and creams (see also Section 6.5). This effect is described in numerous publications. Typical formulations are gels with clotrimazole and triamcinolone. The concentration of 1,2-propylene glycol can range from 5 % to 40 % Solubilizers as absorption enhancers Cremophor RH 40, Lutrol F 68 As these two substances are used to improve solubility in semisolid presentation forms (see Section 6.3), it is highly likely that they will also improve the absorption of the solubilized active ingredients via the skin and mucous membranes in these dosage forms. 146

148 6.5 Solvents in semisolid dosage forms Liquid macrogols Lutrol E grades In semisolid presentation forms, the low molecular weight and liquid macrogols (Lutrol E 300, Lutrol E 400 and Lutrol E 600) are used as solvents or cosolvents in the solubilization process (see also Section 4.4.1), particularly in gels and creams. As an example for the use of Lutrol E 400 as a cosolvent in the solubilization of an insoluble active substance with Cremophor RH 40, the formulation of a tretinoin + dexpanthenol gel is presented in Table 6.5. Table 6.5: Tretinoin + dexpanthenol gel (50 mg + 2,500 mg/100 g) 1. Formulation I. Tretinoin (BASF) 50.0 mg Lutrol E g Cremophor RH g Butylhydroxytoluene 40 mg II. Water 68.4 g Dexpanthenol (BASF) 2.5 g III. Lutrol F g 2. Procedure Add II slowly to the clear solution I at about 40 C. Heat to about 50 C and dissolve about 4 g of III in I/II. Cool to about 6 C and dissolve the rest of III. Maintain at this temperature until the air bubbles have escaped. 3. Properties of the gel A clear yellowish gel was obtained. 4. Chemical stability (12 months, 23 C, dark) Tretinoin: 96 % Dexpanthenol: 100 % 5. Remark It is important to protect the gel from light to avoid the isomerization and degradation of tretinoin. 147

149 Table 6.6 gives the formulation for a metronidazole vaginal gel that contains 40 % Lutrol E 400 as an example for the use of this product as a solvent for the active ingredient. Table 6.6: Metronidazole vaginal gel (1.2%) 1. Formulation I. Metronidazole 1.2 g Lutrol F g Lutrol E g II. Water 37.8 g 2. Procedure Heat mixture I to C and slowly add the water heated to about 70 C. Maintain the temperature until the air bubbles have disappeared. 3. Properties of the gel A clear colourless gel is obtained Propylene glycol Just as in liquid dosage forms, 1,2-propylene glycol is also used in semisolid forms to dissolve the active ingredient. With gels, this is important particularly for their appearance. However, with both creams and gels, it is important both for the absorption (see Section 6.4) and for the feel of the product when it is spread on the skin that the active ingredient should be in the dissolved form. A product that contains crystals is not at all pleasant to spread on the skin. For this purpose, 1,2-propylene glycol is usually diluted with water to a concentration of 5 to 25 %. Above a concentration of 15 % 1,2-propylene glycol, one can also take advantage of its properties as a preservative. Table 6.1 shows a typical formulation for a cream base for a wide range of active substances in which these are dissolved in 8 % 1,2-propylene glycol. Table 6.2 presents a transparent ibuprofen gel that contains, in addition to ethanol, 10 % 1,2-propylene glycol as a solvent for the active substance. 148

150 Table 6.7 gives the formulation for a diclofenac gel cream that contains 15 % 1,2-propylene glycol as a solvent for the active ingredient. Table 6.7: Diclofenac gel-cream (1%) 1. Formulation Diclofenac sodium 1,2-Propylene glycol Miglyol 812 (Dynamit-Nobel) Lutrol F 127 Water 1 g 15 g 10 g 20 g 54 g 2. Procedure Dissolve diclofenac sodium in propylene glycol, add the mixture of water and Miglyol 812. Dissolve Lutrol F 127 in this well stirred mixture at 4 6 C (or at > 70 C). Maintain the temperature until the air bubbles have escaped. 3. Properties White, turbid gel-cream. 149

151 6.6 Carriers for suppositories and ovulae Lutrol E grades The base for most suppositories is usually a solid mixture of fats, but often a blend of different macrogols is also used. This is particularly the case with vaginal ovulae. Macrogols have the advantage that they are soluble in water, so that it is no longer essential that the suppositories should melt at body temperature. Also, the bioavailability of a drug can be much better from a hydrophilic macrogol matrix than from a lipophilic carrier. Usually, two or three grades of macrogol are mixed for this purpose, e.g. Lutrol E 400 or Lutrol E 600 with solid macrogols. Typical examples of drugs that are used in these mixtures include diphenhydramine, indomethacin, metronidazole, acetaminophen and povidone-iodine. Table 6.8 shows a formulation for acetaminophen suppositories. Table 6.8: Acetaminophen suppositories (500 mg) 1. Formulation I. Acetaminophen, fine powder 50.0 g II. Lutrol E g Macrogol g Macrogol g 2. Procedure Melt the mixture II and suspend in it. Cast the melted mass into suppository moulds. 3. Properties of the suppositories Weight 2.0 g Solubility in water readily soluble Color colourless 150

152 6.7 Bioadhesives and film-forming agents for transdermal systems Povidone and copovidone Kollidon 30, Kollidon 90 F, Kollidon VA 64 Because of their excellent adhesive and film-forming properties, both povidone (e.g. Kollidon 25, Kollidon 30 or Kollidon 90 F) and copovidone (Kollidon VA 64) are eminently suitable for use as bioadhesives and filmforming agents in transdermal and transmucosal systems, in much the same way as described in Section 2.5 for buccal tablets for transmucosal absorption. In many cases, povidone is also able to accelerate drug penetration (see Section 6.4.1). The literature gives the following examples of active substances that have been tested with povidone in this application: captopril, diclofenac, dilthiazem, ephedrine, flurbiprofen, indomethacin, isosorbide dinitrate, promethazine, testosterone and verapamil. As Kollidon VA 64 is less hygroscopic and has greater plasticity, it is often preferable to the better-known povidone. Here too, a number of examples of its use can be found in the literature Polyacrylate as carrier film Kollicoat EMM 30 D This polyacrylic dispersion (ethyl acrylate-methyl methacrylate copolymer 2:1) also produces films with good adhesion to the skin and can be used in transdermal therapeutic systems (TTS). A transdermal therapeutic system comprises various layers, a carrier film, a matrix film containing a reservoir of active ingredient and a removable cover film, e.g. made of aluminium. Sometimes, an intermediate adhesive layer can be inserted between the active ingredient matrix film and the cover film in order to improve adhesion to the skin. As Kollicoat EMM 30D forms neutral, adhesive and insoluble polyacrylate films that swell in water and are to some extent permeable to water and active ingredients, it is excellently suited to applications in TTS as an active ingredient matrix layer. As it also contains no functional groups, there is normally no interaction with active ingredient groups. A further advantage of the aqueous dispersion Kollicoat EMM 30D is that organic solvents need not be used. In a similar way to matrix tablets, a high concentration of active ingredient can be used. The speed of active ingredient release from polyacrylate films is dependent on the solubility of the active ingredient and, especially, on its concentration in the polymer and the thickness of the polymer layer. Fig. 6.4 shows the correlation between concentration and matrix film thickness for initial active ingredient concentrations of mg/cm 3 and film thicknesses of 151

153 µm based on in-vitro experiments. Should the percutaneous resorption be slower than the release from the matrix film, the skin becomes the speed-determining factor for bioavailability. Should release from the matrix film be too slow, resorption enhancers such as pore formers or emulsifiers can be added µm Release rate, mg cm -2 d µm 300 µm 400 µm 500 µm Initial drug concentration in the film, mg/cm 2 Fig. 6.4: Active ingredient release from polyacrylate films in transdermal systems as a function of film thickness ( µm) and active ingredient concentration in the film For the manufacture of matrix film containing active ingredient, the active ingredient is suspended or dissolved in dilute aqueous Kollicoat EMM 30D. If required, the viscosity can be adjusted by adding a thickener such as Aerosil 200 (Degussa). Alternatively, other excipients such as emulsifiers can be added. Plasticizers are not required. The continuous manufacture of TTS usually takes place using the so-called blade coating process. The dispersion of active ingredient and Kollicoat EMM 30D is applied to the carrier film as a product layer and dried. It is then applied to the film side of the matrix and covered with a film (e.g. aluminium). Using this process, matrix films up to 0.5 mm thickness can be applied. 152

154 153