genpmd318 hot melt extrusion with basf pharma polymerss3.amazonaws.com/zanran_storage/… · ......
TRANSCRIPT
Hot-Melt Extrusion withBASF Pharma PolymersExtrusion Compendium
K. Kolter, M. Karl, S. Nalawade, N. Rottmann
Pharma Ingredients & Services. Welcome to more opportunities.
BASF_Buch_HotMelt_Buchdecke_Vorab_148x230.indd 3BASF_Buch_HotMelt_Buchdecke_Vorab_148x230.indd 3 27.10.2010 15:59:04 Uhr27.10.2010 15:59:04 Uhr
Hot-Melt Extrusion withBASF Pharma PolymersExtrusion Compendium
K. Kolter, M. Karl, S. Nalawade, N. Rottmann
October 2010
BASF SEPharma Ingredients & Services67056 Ludwigshafen, Germany
10_P_0380_BASF_Buch_HotMelt_1_39.indd 110_P_0380_BASF_Buch_HotMelt_1_39.indd 1 27.10.2010 16:19:03 Uhr27.10.2010 16:19:03 Uhr
10_P_0380_BASF_Buch_HotMelt_1_39.indd 210_P_0380_BASF_Buch_HotMelt_1_39.indd 2 27.10.2010 16:19:03 Uhr27.10.2010 16:19:03 Uhr
1 Introduction to Hot-Melt Extrusion for Pharmaceuticals
2 General Notes on BASF Pharma Polymers
3 Physico-chemical Characteristics – Processability
4 Design of Extrusion Experiments
5 In-Vitro / In-Vivo Characteristics of HME Formulations
6 Manufacture of Final Dosage Forms
7 Flow Chart: From Screening to a Final Pharmaceutical Formulation
8 Practical Recommendations for Extrusion
9 Regulatory Aspects
10 Literature References
11 Alphabetical Index
1
2
3
4
5
6
11
7
8
9
10
10_P_0380_BASF_Buch_HotMelt_1_39.indd 310_P_0380_BASF_Buch_HotMelt_1_39.indd 3 27.10.2010 16:19:03 Uhr27.10.2010 16:19:03 Uhr
4
Contents
1 Introduction to Hot-Melt Extrusion for 8 Pharmaceuticals
2 General Notes on BASF Pharma Polymers 242.1 Kollidon® VA 64 / VA 64 Fine 252.2 Soluplus® 262.3 Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 30 and Kollidon® 90 F 272.4 Kollidon® SR 282.5 Kollicoat® MAE 100P 292.6 Kollicoat® IR and Kollicoat® Protect 292.7 Lutrol® F 127, Lµtrol® micro 127 (Poloxamer 407) and Lutrol® F 68, 31 Lµtrol® micro 68 (Poloxamer 188)2.8 Cremophor® RH 40 322.9 Polyethylene Glycols 33
3 Physico-chemical Characteristics – 34 Processability 3.1 Glass Transition Temperature and Melting Temperature 343.1.1 DSC-Analysis of Pure Polymers and Plasticizers / Solubilizers 343.1.2 DSC-Analysis of Polymer-Plasticizer Mixtures 353.1.3 DSC-Analysis of Polymer Mixtures 373.2 Melt Viscosity 403.2.1 Melt Viscosity of Pure Polymers 413.2.2 Infl uence of Plasticizers on Melt Viscosity 443.3 Decomposition by TGA 453.3.1 TGA of Polymers 463.3.2 TGA of Plasticizers 463.3.3 TGA of Active Pharmaceutical Ingredients 473.4 Specifi c Heat Capacity of Pure Polymers 493.5 API Solubility Enhancement of Pure Polymers 513.6 Calculation of Solubility Parameters of Pure Polymers, 53 Plasticizers and APIs
4 Design of Extrusion Experiments 564.1 Extrusion of Pure Polymers 564.1.1 Extrusion Temperature Range of Pure Polymers 564.1.2 Appearance and Pelletizing Characteristics of Extrudates 584.1.3 Dissolution Characteristics of Polymer Extrudates 624.1.4 Decomposition of Polymers during Extrusion 634.2 Extrusion of Polymer-Plasticizer Combinations 664.2.1 Extrusion Temperature Range of Polymer-Plasticizer Combinations 664.2.2 Appearance and Pelletizing Characteristics of 68 Polymer-Plasticizer Extrudates
10_P_0380_BASF_Buch_HotMelt_1_39.indd 410_P_0380_BASF_Buch_HotMelt_1_39.indd 4 27.10.2010 16:19:04 Uhr27.10.2010 16:19:04 Uhr
5
4.2.3 Miscibility of Polymer-Plasticizer Combinations 704.3 Extrusion of Polymer Mixtures 744.3.1 Extrusion Temperature Range of Polymer Mixtures 744.3.2 Appearance and Pelletizing Characteristics of Extrudates of 78 Polymer Mixtures4.4 Solubilization Capacity of Active Ingredients in Polymers for 79 Hot-Melt Extrusion4.4.1 Film Casting 804.4.2 Extrusion 824.4.3 Results and Comparison 87
5 In-Vitro / In-Vivo Characteristics of 90 HME Formulations5.1 In-Vitro Release Characteristics of HME Formulations 905.2 In-Vivo Behavior of HME Formulations 92
6 Manufacture of Final Dosage Forms 94
7 Flow Chart: From Screening to a 95 Final Pharmaceutical Formulation
8 Practical Recommendations for Extrusion 96
9 Regulatory Aspects 100
10 Literature References 102
11 Alphabetical Index 108
10_P_0380_BASF_Buch_HotMelt_1_39.indd 510_P_0380_BASF_Buch_HotMelt_1_39.indd 5 27.10.2010 16:19:04 Uhr27.10.2010 16:19:04 Uhr
6
10_P_0380_BASF_Buch_HotMelt_1_39.indd 610_P_0380_BASF_Buch_HotMelt_1_39.indd 6 27.10.2010 16:19:04 Uhr27.10.2010 16:19:04 Uhr
7
Acknowledgements
First of all, we would like to thank our colleagues of the R&D Pharma Ingredient Group for their valuable contributions, in particular the members of the Extrusion Team Benjamin Strunk and Ronny Hoffmann.
Our special thanks go to Dr. Angelika Maschke, Dr. Dejan Djuric, Dr. Thorsten Schmeller, Dr. Hendrik Hardung, Dr. Bettina Goldscheid and Timo Münch for their support, proof-reading and constructive discussions.
A special acknowledgement is due to Prof. Dr. Jörg Breitkreutz (Institute for Phar-maceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf, Germany) for his support and for providing the computer program SPWin (version 2.1) for the calculation of the solubility parameters.
Finally, we wish to thank all other persons who were involved in the compilation of this extrusion compendium.
10_P_0380_BASF_Buch_HotMelt_1_39.indd 710_P_0380_BASF_Buch_HotMelt_1_39.indd 7 27.10.2010 16:19:09 Uhr27.10.2010 16:19:09 Uhr
8
1 Introduction to Hot-Melt Extrusion for Pharmaceuticals
In recent years, interest in hot-melt extrusion techniques for pharmaceutical applica-tions has grown signifi cantly. Hot-melt extrusion (HME) is an established manufactu-ring process that has been used in the plastics and food industry since the 1930s. In the 1980s, BASF SE was the fi rst to apply the melt extrusion process based on polymers with a high glass transition temperature (such as polyvinylpyrrolidones) to pharmaceuticals [1]. Later on, Soliqs, the drug delivery business unit of Abbott GmbH & Co KG, commercialized the technology and subsequently launched several drugs [2]. A number of research groups have demonstrated HME processes as being viable techniques for the preparation of pharmaceutical drug delivery systems, including granules [3, 4], pellets [5, 6], sustained release tablets [7, 8, 9, 10, 11], transdermal and transmucosal drug delivery systems [12, 13, 14, 15, 16, 17, 18, 19, 20] and implants [21, 22, 23, 24]. The HME technique is an attractive alternative to traditional processing methods [25]. Examples for solving pharmaceutical challenges via HME are given in Table 1-1.
Table 1-1 Advantages of hot-melt extrusion
Hot-melt extrusion is currently generating more and more interest as the percentage of poorly soluble new chemical entities in drug development is constantly increasing. For such molecules, hot-melt extrusion offers an opportunity to make them orally bioavailable [26]. Additional benefi ts are the creation of a reliable drug release profi le and a robust manufacturing process which can be run in practically any pharmaceu-tical factory. However, as with other breakthrough innovations, numerous obstacles had to be overcome before the technology and resulting dosage forms could be commercially exploited. Compared with other pharmaceutical technologies such as
Problem
Poor (low / unreliable) bioavailability due to poor API solubility
Use of Hot-Melt Extrusion to prepare solid solution / dispersion or SEDDS (enhanced dissolution)
Poor API stability during processing caused by hydrolysis
Use of Hot-Melt Extrusion as alternative to wet agglomeration (no hydrolytic stress)
Unreliable sustained release actionUse of Hot-Melt Extrusion to prepare sustained release dosage form (single / multiple units)
Poor stability or tolerability of API in the stomachUse of Hot-Melt Extrusion to prepare enteric dosage forms (single / multiple units)
Poor taste of the APIUse of Hot-Melt Extrusion to prepare taste-masked dosage forms
Manufacturing of fi lmsUse of Hot-Melt Extrusion to prepare oral strips or dermal patches
Solution by HME
10_P_0380_BASF_Buch_HotMelt_1_39.indd 810_P_0380_BASF_Buch_HotMelt_1_39.indd 8 27.10.2010 16:19:11 Uhr27.10.2010 16:19:11 Uhr
9
tableting, hot-melt extrusion is still an emerging technology and its potential has not yet been fully explored. The technology itself can be defi ned as a process where a material which melts or softens under elevated temperatures and pressures is forced through an orifi ce by screws. A prerequisite of the polymer to be used in hot-melt ex-trusion is appropriate thermoplastic behavior; however, the number of such polymers approved for pharmaceutical use is limited. BASF offers a range of polymers with different structures and properties for use in hot-melt extrusion.
The extrusion processExtruders for pharmaceutical use have been designed and adapted for mixing drugs with carriers in various dosage forms. The signifi cant difference between extruders for thermoplastics and pharmaceutical applications is the equipment used and hence the contact surface, which must meet regulatory requirements. The contact parts of the extruders used in pharmaceuticals must not be reactive nor may they release components into the product. The extruder equipment is specially confi gured to fulfi ll all cleaning and validation standards applicable to the pharmaceutical industry.
In principle, an extruder consists of barrels enclosing single or twin screws which transport and subsequently force the melt through a die, giving it a particular shape. The barrel can be heated to the desired temperature. Due to the external heat and shear provided by the screws, the polymer is plasticized and hence its viscosity re-duced. Since the extruder is fed at one side and the extruded material exits from the other side, it is a typical continuous process; this makes it even more attractive for pharmaceuticals [27]. The hot-melt extrusion process comprises the steps melting, mixing and shaping (see Figure 1-1).
The purpose of the feeding section is to transfer the materials from the feeder to the barrel. The polymer mixture typically begins to soften in the melting zone. The melt moves by circulation in a helical path by means of transverse fl ow, drag fl ow, pressure fl ow and leakages [25]. Thermoplastic polymers primarily exist in a molten state when entering the shaping section. The function of this zone is to reduce the pulsation fl ow and ensure a uniform delivery rate through the die. At the end of the barrels, the at-tached die dictates the shape of the extrudates.
1
10_P_0380_BASF_Buch_HotMelt_1_39.indd 910_P_0380_BASF_Buch_HotMelt_1_39.indd 9 27.10.2010 16:19:12 Uhr27.10.2010 16:19:12 Uhr
Powder
Die Tempering Cylinder Screw
EngineExtrudate
10
Figure 1-1 Principle of hot-melt extrusion
The complete extrusion set-up con-sists of three distinct parts: A conveying and kneading system for material transport and mixing
A die system for forming the extru-dates
Downstream auxiliary equipment (coo-ling, pelletizing and collecting)
The components of the extruder are: The feed hopper (gravimetric or volu-metric feeding)
Temperature-controlled barrels (hea-ting and / or cooling)
Die (different die confi gurations are available)
Modifi ed according to: M. Thommes, Systematische Untersuchungen zur Eignung von kappa-Carrageenan als Pelletierhilfsstoff in der Feuchtextrusion / Sphäronisation, Ph. D. Thesis, University of Düsseldorf, 2006.
Shaping Mixing Melting
Temperature: above Tg of polymer (60 – 180 °C)Residence time: variable (0.5 – 5 min)
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1010_P_0380_BASF_Buch_HotMelt_1_39.indd 10 27.10.2010 16:19:12 Uhr27.10.2010 16:19:12 Uhr
11
Figure 1-2 Twin-screw extruders
Additional equipment: Process analytical technology (e.g.
spectroscopic systems) Vacuum pumps for degassing ex-
trudates Pelletizer equipment Calendering equipment
In-process control parameters can be: Zone and die temperatures Screw speed Torque or power consumption Pressure Melt viscosity Feed rate
Extruders are available as single- or mul-ti-screw versions. Twin-screw extruders utilize two screws usually arranged side by side. The use of two screws allows a number of different confi gurations to be obtained and imposes different condi-tions on all zones of the extruder. In the twin-screw extruder, the screws can eit-her rotate in the same (co-rotating) or in the opposite (counter-rotating) direction [25].
Co-rotating extruders are the most im-portant types for industrial applications. They can be operated at high screw speeds and high output and provide good mixing and conveying characte-ristics as well as more fl exibility in screw design. The co-rotating and counter-rotating twin-screw extruders can be classifi ed as either non-intermeshing or intermeshing. In most cases, co-rotating intermeshing twin-screw extruders are used. The main advantages of sing-le- and twin-screw extruders are listed below.
Advantages of twin-screw compared to single-screw extruders [25]: Easier material feeding High kneading potential High dispersing capacities Less tendency to overheat (important for sensitive APIs)
Shorter and constant residence times
Co-rotating High screw speed, high output More fl exibility in screw design
Counter-rotating Low screw speed, low output High shear forces High pressure between the screws Air entrapment
Modifi ed according to: Thermo Fisher Scientifi c Inc.
1
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1110_P_0380_BASF_Buch_HotMelt_1_39.indd 11 27.10.2010 16:19:14 Uhr27.10.2010 16:19:14 Uhr
12
Advantages of single-screw compared to twin-screw extruders: Mechanical simplicity Low cost of investment
The major advantages of the twin-screw extruders are in their conveying and trans-port mechanisms and in their mixing abilities compared to the single-screw extruders. This is why applications are continuing to expand within the pharmaceutical fi eld.
Conveying and kneading elementsMost extruders have a modular design to facilitate different screw confi gurations. The confi guration of the screw has a signifi cant impact on the extrusion process and can be designed to achieve either a high or a low shear. The length of the screws in the extrusion process is given in terms of L / D ratio (length of the screw divided by the screw diameter) [28, 29].
The confi guration of the screws can be varied by number and arrangement of convey-ing and kneading elements (see Figure 1-3) [26].
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1210_P_0380_BASF_Buch_HotMelt_1_39.indd 12 27.10.2010 16:19:15 Uhr27.10.2010 16:19:15 Uhr
13
Profi les with open chambers: In the feeding sections For melt exchange For degassing (venting)
Profi les with closed chambers: For high pressure build-up In front of kneading elements
Kneading elements are used to introduce shear energy to the extruded materials.
The elements are arranged in different offset angles (30°, 60° and 90°) used for:
Plasticizing Mixing Dispersing
Figure 1-3 Screw elements, their application and effects on the extrusion process
Kneading elements
Conveying elements
Kneading elements
30° 60° 90°
Conveying element
1
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1310_P_0380_BASF_Buch_HotMelt_1_39.indd 13 27.10.2010 16:19:15 Uhr27.10.2010 16:19:15 Uhr
14
The design of the kneading elements has an infl uence on the mixing behavior within the extrusion process. The advance angle also determines the conveying ability of the element ranging from forwarding (30° and 60°) and neutral (90°) to reversing (30° reverse) character. Neutral elements (90°) push material neither forwards nor back-wards. Irrespective of the reverse-fl ighted element, ability for mixing and shearing of the material increases the higher the advance angle. Reverse-fl ighted kneading blocks have a retaining character and are usually utilized when substantial mechanical stress has to be exerted onto the material [4].
FeedingPowder or granules are usually gravimetrically dosed into the extruder. The material is heated and more or less melted in the fi rst part. Thereafter, the material is mixed and homogenized by the kneading elements, and, at the end, extruded through a die which can have various shapes. Residence times in the extruder vary depending on the size of the extruder, screw speed, screw confi guration and feed rate. They range typically from 0.5 to 5 minutes.
The feeding mode of the feeders can be gravimetric and volumetric. Gravimetric fee-ding is typically specifi ed for c-GMP installations.
Feeders for pharmaceutical materials have the following characteristics: They are easy to clean and disassemble Stainless steel components are used Stainless steel shrouding is used for non-stainless-steel parts Qualifi cation documentation is available
Gravimetric feeding Screw rotation speed is adjusted to keep the
mass-fl ow rate constant (quantity per unit of time) Gravimetric feeding is typically specifi ed for GMP
installations
Table 1-2 Feeder and feeding modes
Volumetric feeding Used as refi ll devices for gravimetric feeders High fl uctuation in the mass-fl ow rate for metering
dry ingredients into the extruder (variations in ma-terial bulk density because of handling / variations in screw fl ight loading)
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1410_P_0380_BASF_Buch_HotMelt_1_39.indd 14 27.10.2010 16:19:17 Uhr27.10.2010 16:19:17 Uhr
15
Figure 1-4 Pelletizer
Downstream processingDownstream extrusion equipment is used to fi nish, shape and analyze the extruded product. After leaving the die in the form of continuous strands or ribbons, cooling and cutting is performed, resulting in the required particle size. Process Analytical Technology (PAT) instruments such as in-line NIR (Near Infrared Spectroscopy) can be used to check the homogeneity of the active ingredient in the extrudate.
Examples of downstream systems are: Cooling of the extrudates with air or nitrogen on stainless steel conveyors or PTFE or in a non-solvent medium
Shaping devices (calender, pelletizing device, Figure 1-4) Film and lamination systems for transmucosal/transdermal applications Cyclic molding Chill rolls and torque winders for cooling and collecting the extrudates
1
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1510_P_0380_BASF_Buch_HotMelt_1_39.indd 15 27.10.2010 16:19:17 Uhr27.10.2010 16:19:17 Uhr
Resi
denc
e tim
e [s
]
300
250
200
150
100
50
0250 500 750 1000 1250
Feed rate [g/h]
100 RPM200 RPM300 RPM400 RPM500 RPM
16
Process variables of twin-screw extrusionProcess variables in twin-screw extrusion can be divided into step and continuous changes. Continuous changes include modifi cations during the running process and step changes require off-line modifi -cations (Table 1-3).
Table 1-3 Variables in twin-screw extrusion
Step changes: Screw design Die design Barrel layout
Continuous changes: Screw speed Feed rate Barrel temperature
Screw speed, feed rate and barrel temperature are the most relevant process para-meters in twin-screw extrusion. These parameters particularly infl uence the system parameters mechanical energy, residence time and the temperature of the material.
The correlation of the feed rate and screw speed on the residence time of Kollidon® VA 64 in a 16 mm twin-screw extruder (length to diameter ratio of 40) at 170 °C is illustrated in Figure 1-5. The residence time was determined by measuring the time for conveying a colored additive such as Kollicoat® IR Red and Kollicoat® IR Brilliant Blue from the feeding section to the die exit.
Figure 1-5 Example of residence time in a 16 mm twin-screw extruder
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1610_P_0380_BASF_Buch_HotMelt_1_39.indd 16 27.10.2010 16:19:20 Uhr27.10.2010 16:19:20 Uhr
17
1On increasing feed rate and screw speed, the residence time of the material decre-ased and the torque of the machine increased. At higher temperatures, the torque decreased due to a lowering of the melt viscosity of the polymer (Figure 1-6).
Figure 1-6 Effect of feed rate, screw speed and temperature on HME
Drug delivery systemsHot-melt extrusion is mainly used to formulate poorly soluble actives as solid disper-sions [30, 31]. Of the various types of solid dispersions, 3 are relevant for pharmaceu-tical applications since the applied polymers are usually amorphous. Principally, the drug can be either dissolved or dispersed whilst in an amorphous or crystalline state. A thermodynamically stable formulation (Figure 1-7) is achieved when the drug is completely dissolved below its saturation solubility in the polymer, resulting in a solid solution. When the drug concentration exceeds the saturation solubility, the whole system is only kinetically controlled since the drug may crystallize or precipitate out of the polymer during storage. Formulation in the middle is also kinetically controlled. This is because the amorphous drug is dispersed in an amorphous polymer and as the drug may crystallize, defi nitely changing the dissolution and biopharmaceutical properties. The system on the left is quite stable – in this case the polymer contains crystalline drug – because only Ostwald ripening can occur, leading to larger crystals. However, this is not very pronounced due to the low diffusivity of the drug in a solid polymer.
Feed rate [kg/h]
Screw speed [rpm]
Temperature [°C]
TorqueResidence time
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1710_P_0380_BASF_Buch_HotMelt_1_39.indd 17 27.10.2010 16:19:20 Uhr27.10.2010 16:19:20 Uhr
Drug Crystalline
Polymer
Thermo-dynamicstability
AmorphousMolecularlydissolved
Amorphous Amorphous Amorphous
Almost stableUnstable
(kinetically controlled)
Stable(drug below
saturation solubility)
18
Figure 1-7 Relevant types of solid dispersions
Based on the pH-dependant solubility of the polymer, instant-release (IR), enteric or sustained-release (SR) drug delivery systems can be developed. The selection of the polymer strongly determines the release rate of the drug (Figure 1-8). In most cases, instant-release systems have been developed and commercialized so far.
IR
Kollidon® VA 64Soluplus®
Kollidon® gradesKollicoat® IRKollicoat® ProtectLutrol® F grades
SR
Kollidon® SR
Enteric
Kollicoat® MAE 100P
Figure 1-8 Application fi elds of BASF pharma polymers
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1810_P_0380_BASF_Buch_HotMelt_1_39.indd 18 27.10.2010 16:19:20 Uhr27.10.2010 16:19:20 Uhr
19
1Polymers for hot-melt extrusionThe polymer must exhibit thermoplastic characteristics in order to enable the hot-melt extrusion process and it must be thermally stable at the extrusion temperatures employed. Other relevant characteristics are: suitable Tg or Tm (50 – 180 °C), low hygroscopicity and no toxicity since larger amounts of polymer are used (Figure 1-9). Polymers with a high solubilization capacity are particularly suitable because large quantities of drugs can be dissolved. Some features like lipophilicity, hydrogen bon-ding acceptors or donors [32] and amide groups are basic prerequisites for a high so-lubilization capacity; the same applies to organic solvents (Figure 1-10). This explains why povidone, copovidone and Soluplus® are highly suitable for hot-melt extrusion. Copovidone and Soluplus® in particular are much more lipophilic than many other water-soluble polymers containing hydroxyl groups and, therefore, is best suited to the lipophilicity of poorly soluble drugs. In addition, the solubility parameter can be used to determine whether actives and polymers are compatible [33, 34].
Figure 1-9 Basic requirements for polymers used in HME
Thermoplastic behavior deformability is essentialSuitable Tg 50 – 180 °CHigh thermal stability 50 – 180 °CLow hygroscopicity prevents crystallizationNo toxicity application of large amountsHigh or no solubilization thermodynamically stablecapability formulation
10_P_0380_BASF_Buch_HotMelt_1_39.indd 1910_P_0380_BASF_Buch_HotMelt_1_39.indd 19 27.10.2010 16:19:20 Uhr27.10.2010 16:19:20 Uhr
20
Impact on solubilization capability Lipophilicity Solubility parameter Hydrogen bonding Amide structures acting as hydrogen bond acceptors
Excellent solvents Dimethyl acetamide Dimethyl formamide Pyrrolidone Methyl pyrrolidone
Poor solvents Methanol Acetone
Excellent polymers Soluplus®
Kollidon® VA 64 Kollidon® 30
Poor polymers Kollicoat® IR HPCC O
C OH
N C
O
Similia similibus solvuntur
Figure 1-10 Solubilization capability
When the drug is incorporated in a supersaturated form, the whole mixture should have a very rigid structure in order to minimize crystallization either from dissolved drug or from amorphous drug particles [35]. The formulation, being a solid solution, dissolves in gastric or intestinal fl uids forming a supersaturated solution of the drug in these aqueous media, thus enhancing dissolution and bioavailability [36].
Extrudability is mainly determined by the glass transition or melting temperature and melt viscosity [37]. Materials of high molecular weight generate a high melt viscosity and are diffi cult to extrude. A high glass transition or melting temperature requires high processing temperatures, which can degrade sensitive drugs. As a general rule, extrusion processes can be run at temperatures 20 – 40 °C above glass transition temperature. Most polymers demonstrate thixotropic behavior, which means that the viscosity reduces as a function of increasing shear stress.
Plasticizers added to the polymer can reduce glass transition temperature and melt viscosity, thus facilitating the extrusion process [38]. Some actives may also have a plasticizing effect.
An extrusion temperature range of 90 – 140 °C for a drug containing polymer seems to be best, since the drug should survive thermal stress lasting for 0.5 – 5 minutes in a non-aqueous environment.
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2010_P_0380_BASF_Buch_HotMelt_1_39.indd 20 27.10.2010 16:19:21 Uhr27.10.2010 16:19:21 Uhr
Crystallinedrug
Hot-meltextrusion
Solid solutionextrudate
Tablets
+ Temp.+ Polymer
21
1In extruded drug delivery systems, the polymer serves as a matrix and, in conse-quence, larger quantities are required than in its more common use as a binder or coating agent. It is crucial that the polymers are non-toxic and approved in various countries at high doses. Kollidon® VA 64 completely fulfi lls this requirement. Based on toxicological studies, other polymers may also be used in high doses; however, these have not yet been approved in such doses. The regulatory status of the BASF pharma polymers is summarized in chapter 9 of this compendium.
Advantages of hot-melt extrusion in detailWithin the pharmaceutical industry hot-melt extrusion has been used for various pur-poses, such as: Enhancement of the dissolution rate and bioavailability of a drug Controlling or modifying drug release Taste masking Stabilizing the API Parenteral depots and topical delivery systems
Increasing dissolution rate and bioavailability of APIs that are poorly soluble in water are important challenges in dosage form development (Figures 1-11 and 1-12). One approach is the formation of a solid solution /dispersion of a drug with hydrophilic excipients. The solid solution is the ideal type for increasing drug release. In this for-mulation, the drug is molecularly dissolved and has a lower thermodynamic barrier for dissolution [39].
Figure 1-11 From poor API solubility to a fi nal formulation
Polymer matrix acts as a solid solvent for drug molecules In the ideal case, the drug is molecularly dissolved in the polymer Enhanced rate of dissolution and solubility of drug molecules compared
to the crystalline form
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2110_P_0380_BASF_Buch_HotMelt_1_39.indd 21 27.10.2010 16:19:21 Uhr27.10.2010 16:19:21 Uhr
22
Powder mixing
Melt extrusion
Pelletizing / millingDirect shaping(Calendering)
Tableting orcapsule filling
Spheronisation
Tableting orcapsule filling
Figure 1-12 Hot-melt extrusion for pharmaceutical dosage forms
Once developed, hot-melt extrusion is a reliable and robust process offering benefi ts in cost-effi ciency. Compared to other processes for the production of solid solutions, it is far less complex, since the manufacturing of such dosage forms requires only a few steps and avoids the use of organic solvents.
Hot-melt extrusion also has advantages over solvent-based methods of forming solid solution /dispersions: No need to handle explosive solvents Absence of residual solvents Continuous processing possible Possibility of continuous processing Fewer process steps High product density Non-dusty pellets (e.g. for HAPI formulations) Small-scale equipment Non-aqueous process
Besides oral drug formulations, the hot-melt extrusion technique can be employed to manufacture parenteral depots such as injectible implants and stents and topical delivery systems such as dermal or transdermal patches. For these applications, the extrusion process is often combined with a shaping step or injection molding.
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2210_P_0380_BASF_Buch_HotMelt_1_39.indd 22 27.10.2010 16:19:21 Uhr27.10.2010 16:19:21 Uhr
23
1Injection molding combined with hot-melt extrusionExtrusion is a process for producing materials with defi ned physical and mechanical properties, while injection molding is a suitable process for shaping and sizing these materials to different forms for fi nal applications. Injection molding has traditionally been used for producing parts with different sizes and different shapes from both thermoplastic and thermosetting materials. In this process, materials in the form of powder or granules are fed into a heated barrel. The barrel contains a screw which can convey and mix (the degree of mixing is not comparable to extrusion) the ma-terials. The barrel is heated externally and the heat is transferred from the barrel to the screw and hence to the materials. Due to the reciprocating action of the screw, the melt is forced by pressure into a mold cavity attached to the end of the screw. The melt cools down in the mold and acquires a defi ned shape. After solidifi cation, product is released by opening the mold. Molds are generally made of steel or alu-minum. The process looks simple in terms of its principle, but is complex in terms of process parameters.
The injection molding process is generally influenced by the following parameters: Material type (crystalline, semi-crystalline or amorphous) Screw (also barrel) material and its design Mold material and its design Physical properties of the melt and its solid form Cycle time
Although injection molding was already introduced by Speiser in 1964 as a phar-maceutical technology to produce sustained-release dosage forms [40], its use within the pharmaceutical industry has been limited to date to a few specifi c applications. A study of the literature shows that some groups have been actively involved in uti-lizing the potential of injection molding for pharmaceutical applications and medi-cal devices. One of the studies includes the development of polyethylene [41] and polyethylene glycol matrices [42] and the use of soy protein in injection [43] and co-injection-molded [44] matrices. Eith et al. evaluated the development of an injection-molded starch capsule [45]. Egalet®, a novel drug delivery system prepared using injection molding, consists of an impermeable shell of cetostearyl alcohol and ethyl cellulose enclosing a matrix plug composed of drug, polyethylene glycol monostea-rate and polyethylene oxide, drug release being controlled by modulating the erosion of the matrix [46]. Recently, in order to produce sustained-release matrix tablets, hot-melt extrudates of ethyl cellulose as a release-controlling polymer and hydroxypropyl methylcellulose as a hydrophilic drug release modifi er together with different drugs such as ibuprofen and metoprolol tartrate were molded into tablets using a lab-scale injection molder operating at the same temperature as the extruder [47, 48].
Apart from tablet applications, considering the broad window of injection molding for different thermoplastics and biodegradable polymers, pharmaceutical polymers can be molded into fi lms, rods, rings and shaped implants.
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2310_P_0380_BASF_Buch_HotMelt_1_39.indd 23 27.10.2010 16:19:22 Uhr27.10.2010 16:19:22 Uhr
24
2 General Notes on BASF Pharma Polymers
BASF SE offers a variety of polymers based on different monomers and chemical structures which can be employed in hot-melt extrusion applications. The portfolio comprises homopolymers, copolymers, amphiphilic copolymers as well as solubili-zers and plasticizers, which are described in this chapter in more detail [49, 50, 51]. Solutol® HS 15 and Cremophor® EL can also be used in hot-melt extrusion but are not described here in detail.
Table 2-1 List of BASF pharmaceutical excipients suitable for hot-melt extrusion and their pharmacopoeial monographs
Exipient Ph. Eur. Monograph USP-NF Monograph
Kollidon® VA 64 Copovidone Copovidone
Soluplus® - -
Kollidon®12 PF Povidone (K-value 12) Povidone (K-value 12)
Kollidon® 17 PF Povidone (K-value 17) Povidone (K-value 17)
Kollidon® 30 Povidone (K-value 30) Povidone (K-value 30)
Kollidon® 90 F Povidone (K-value 90) Povidone (K-value 90)
Kollidon® SR - -
Kollicoat® MAE 100P Methacrylic acid –ethacrylate copolymer 1:1
Methacrylic acid copolymer type C
Kollicoat® IR Macrogol polyvinyl alcohol grafted copolymer
Ethylene glycol and vinyl alcohol graft copolymer
Kollicoat® Protect Macrogol polyvinyl alcohol grafted copolymer + poly(vinyl alcohol)
Ethylene glycol and vinyl alcohol graft copolymer + polyvinyl alcohol
Lutrol® F 127 / Lµtrol® micro 127
Poloxamer 407 Poloxamer 407
Lutrol® F 68 / Lµtrol® micro 68
Poloxamer 188 Poloxamer 188
Lutrol® E grades Macrogols Polyethylene glycols
Cremophor® RH 40 Macrogolglycerol hydroxy-stearate 40
Polyoxyl hydrogenated castor oil
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2410_P_0380_BASF_Buch_HotMelt_1_39.indd 24 27.10.2010 16:19:22 Uhr27.10.2010 16:19:22 Uhr
CH
N O
n m
CH
O
CH2 CH2
C
CH3
O
25
2.1 Kollidon® VA 64 / VA 64 Fine
The Kollidon® VA 64 grades are manufactured by free-radical polymerization of 6 parts of N-vinylpyrrolidone and 4 parts of vinyl acetate. Vinylpyrrolidone is a hydrophilic, wa-ter-soluble monomer whereas vinyl acetate is lipophilic and water-insoluble. The ratio ofboth monomers is balanced in such a way that the polymer is still freely water soluble.
Properties Vinylpyrrolidone / vinyl acetate
60 / 40 Appearance
White or slightly yellowish free fl owing powder
Molecular weight ~ 55000 g / mol
K-value (1 % in water) 25 – 31
Solubility Solutions of up to 50 % can be prepared: water, ethanol, isopropanol, methanol,
DMF, methanol / acetone (1:1, w / w %), ethanol / acetone (1:1, w / w %)Solutions of up to 25 % can be prepared: acetoneSolutions of > 10 % can be prepared: methylene chloride, glycerol, propylene glycol
Less soluble in: ether, cyclic, aliphatic and alicyclic hydrocarbons
Figure 2.1-1 Properties and structural formula of Kollidon® VA 64
Pharmaceutical applications in addition to HME:Kollidon® VA 64 is used in the pharmaceutical industry as a binder in the production of granules and tablets by wet granulation, as a dry binder in direct compression, as an additional fi lm former in coatings on tablets, as a protective layer and sub-coat for tablet cores and as a fi lm-forming agent in sprays.
Intended release profi le of extrudates:Since Kollidon® VA 64 is quite soluble in aqueous media, the release profi le of these formulations is mostly instant release; however, it can also be used in modifi ed release drug delivery systems.
2
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2510_P_0380_BASF_Buch_HotMelt_1_39.indd 25 27.10.2010 16:19:22 Uhr27.10.2010 16:19:22 Uhr
HO
O
O
O
HO
n
mOO
ON
l
60
50
40
30
20
10
0Acetone Ethanol DMF Methanol MeOH/
Acetone(1:1 w/w%)
EtOH/Acetone
(1:1 w/w%)
26
2.2 Soluplus®
Soluplus® is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copo-lymer. It has an amphiphilic structure and can be regarded as a polymeric solubilizer. This innovative excipient was launched in 2009 and was designed to be used in hot-melt extrusion and to solubilize poorly soluble actives.
Properties PEG 6000 / vinylcaprolactam / vinyl acetate
13 / 57 / 30 Appearance
White to yellowish free fl owing granules Molecular weight
~ 118000 g / mol K-value (1 % in ethanol)
31– 41 Solubility
Soluble in water and many organic solvents (see Figure 2.2.2)
Figure 2.2-1 Properties and structural formula of Soluplus®
Figure 2.2-2 Solubility of Soluplus® in organic solvents
Conc
entr
atio
n of
Sol
uplu
s® [%
]
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2610_P_0380_BASF_Buch_HotMelt_1_39.indd 26 27.10.2010 16:19:22 Uhr27.10.2010 16:19:22 Uhr
ON
n
27
Pharmaceutical applications in addition to HME:Soluplus® acts as a matrix polymer for solid solutions prepared for instance by spray drying or evaporation techniques. It can also be used as a wet or dry binder, fi lm former in oral strips, solubilizer, emulsion stabilizer and protective colloid. In most of those applications it improves the formulation characteristics by its outstanding solubilizing effect. Furthermore, Soluplus® can increase the bioavailability of poorly soluble drugs.
Intended release profi le of extrudates:Soluplus® is expected to show an instant release profi le.
2.3 Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 30 and Kollidon® 90 F
The soluble Kollidon® grades are obtained by free-radical polymerization of vinylpyr-rolidone. The current range of soluble Kollidon® grades consists of pharmaceutical grade products with different nominal K-values.
Kollidon® grade MW [g / mol]K-value (1 or 5 % solutions in water)
Kollidon® 12 PF ~2500 11 – 14
Kollidon® 17 PF ~9000 16 – 18
Kollidon® 30 ~50000 28 – 32
Kollidon® 90 F ~1250000 85 – 95
Table 2.3-1 Molecular weight (MW) values and K-values for different grades of Kollidon®
Figure 2.3-1 Properties and structural formula of polyvinylpyrrolidone (povidone)
Properties Polyvinylpyrrolidone Appearance
Almost white free fl owing powder Solubility
Solutions of > 10 % can be prepared: water, methanol, isopropanol, chloroform, n-butanol, cyclohexanol, n-propanol, ethanol, polyethy-lene glycol 400, glycerine, propylene glycol, methylene chloride, triethanolamine
Less soluble (< 1 %) in: cyclohexane, pentane, diethyl ether, carbon tetrachloride, ethyl acetate, toluene, liquid paraffi n, xylene
2
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2710_P_0380_BASF_Buch_HotMelt_1_39.indd 27 27.10.2010 16:19:23 Uhr27.10.2010 16:19:23 Uhr
CH
N O
mn
CH
O
CH2CH2
C
CH3
O
28
Pharmaceutical applications in addition to HME:The general properties of the soluble Kollidon® grades in pharmaceuticals are solu-bility in all conventional solvents, adhesive and binding power, fi lm formation, affi nity to hydrophilic and hydrophobic surfaces, ability to form water-soluble complexes and thickening properties.
Intended release profi le of extrudates:All PVP powders are quite water-soluble and therefore intended to be used for instant release dosage forms.
2.4 Kollidon® SR
Kollidon® SR is a spray-formulated mixture of polyvinyl acetate and polyvinylpyrrolido-ne (povidone) in the ratio 8:2.
Pharmaceutical applications in addition to HME:Kollidon® SR can be used for the production of sustained release matrix preparations in the form of tablets, pellets and granules. The recommended technology for the production of sustained release matrix tablets based on Kollidon® SR is direct com-pression, but also roller compaction and wet granulation can be used.
Intended release profi le of extrudates:Kollidon® SR is insoluble in water and is expected to deliver the active in a sustained release manner [52, 53].
Figure 2.4-1 Properties and structural formula of Kollidon® SR
Properties Polyvinyl acetate / polyvinylpyrrolidone
80 / 20 Appearance
White or slightly yellowish, free fl owing powder Molecular weight
Polyvinyl acetate: ~ 450000 g / mol Povidone: ~ 50000 g / mol
K-value (1% in tetrahydrofuran) 60 – 65
Solubility Soluble in N-methylpyrrolidone, acetone, methanol Insoluble in water, ethanol, isopropanol
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2810_P_0380_BASF_Buch_HotMelt_1_39.indd 28 27.10.2010 16:19:23 Uhr27.10.2010 16:19:23 Uhr
CH2 C
COOHn
CH3
CH2 CH
COOC2H5m
29
2.5 Kollicoat® MAE 100P
This copolymer consists of methacrylic acid and ethyl acrylate in a ratio of 1:1. It is an anionic copolymer that can be neutralised by bases such as sodium hydroxide.
Pharmaceutical applications in addition to HME:The main application of Kollicoat® MAE 100P is as a fi lm former in enteric coatings for solid dosage forms such as enteric tablets and pellets.
Intended release profi le of extrudates:Kollicoat® MAE 100P is intended to be used as an enteric matrix in hot-melt extrusion formulations, the drug being released mainly in the intestine.
2.6 Kollicoat® IR and Kollicoat® Protect
Kollicoat® IR powder (Polyvinyl alcohol – polyethylene glycol graft copolymer) com-prises polyethylene glycol and polyvinyl alcohol in the ratio of 25:75 (w / w %). The po-lyethylene glycol chain forms a backbone onto which side chains of polyvinyl alcohol are grafted.
Kollicoat® Protect is a formulated mixture of Kollicoat® IR and polyvinyl alcohol.
Figure 2.5-1 Properties and structural formula of Kollicoat® MAE 100P
Properties Methacrylic acid / ethyl acrylate
50 / 50 Appearance
White redispersible powder with a faint characteristic odor
Molecular weight ~ 250000 g / mol
Solubility Dissolves in slightly alkaline, aqueous media;
readily soluble in ethanol, methanol
2
10_P_0380_BASF_Buch_HotMelt_1_39.indd 2910_P_0380_BASF_Buch_HotMelt_1_39.indd 29 27.10.2010 16:19:23 Uhr27.10.2010 16:19:23 Uhr
CH2 O O OCH2 CH2 CH2 CH2O O OCH
CH2
CHCH2 CH2 CH2
CH OH
CH2
CH OH
CH2
CH OH
CH2
CH OH
30
Figure 2.6-1 Properties and structural formula of Kollicoat® IR
Figure 2.6-2 Properties of Kollicoat® Protect
Properties Polyvinyl alcohol / polyethylene glycol
75 / 25 Appearance
White to faintly yellow free fl owing powder Molecular weight
~ 45000 g / mol Solubility
Water, weak acid / weak bases (up to 40 %) Ethanol + water (1:1) (up to 25 %) Practically insoluble in 96 % ethanol and non-polar solvents
Properties Kollicoat® IR / polyvinyl alcohol
60 / 40 Appearance
White to off-white free fl owing powder Molecular weight
~ 30000 g / mol
Pharmaceutical applications in addition to HME:Kollicoat® IR acts as a fl exible fi lm forming agent in instant release coatings, as a water-soluble binding agent in wet granulation, as a pore-forming agent for adjusting release rates, as a fi lm former in oral strips, as a protective colloid and as a stabilizer of emulsions and suspensions. Kollicoat® IR combines enormous fl exibility with ext-remely low viscosity in water.
Kollicoat® Protect can be used as a protective fi lm against oxidation and hydrolysis of the active ingredient. It can be used to mask taste, to facilitate the swallowing of tab-lets, to improve their appearance or as a sub-coating. Kollicoat® Protect possesses all the advantages of Kollicoat® IR, e.g. rapid dissolution in water, a high degree of adhesion, also on lipophilic surfaces, enormous fl exibility and low viscosity in water.
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3010_P_0380_BASF_Buch_HotMelt_1_39.indd 30 27.10.2010 16:19:23 Uhr27.10.2010 16:19:23 Uhr
HO CH2 CH2 Oa
CH2 CH2 OaHCH2 CH
CH3
Ob
31
Intended release profi le of extrudates:Due to the good water solubility of Kollicoat® IR and Kollicoat® Protect, an instant release profi le can be expected [54].
2.7 Lutrol® F 127, Lµtrol® micro 127 (Poloxamer 407) and Lutrol® F 68, Lµtrol® micro 68 (Poloxamer 188)
The Lutrol® F grades F 68 / F 127 and Lµtrol® micro 68 / micro 127 are synthetic co-polymers of ethylene oxide (a) and propylene oxide (b) where a = approx. 80 and b = approx. 27 for Lutrol® F 68 / Lµtrol® micro 68 and a = approx. 101 and b = approx. 56 for Lutrol® F 127 / Lµtrol® micro 127. Principally, the Lutrol® grades are amphip-hilic molecules where polyoxypropylene represents the lipophilic and polyethylene glycol the hydrophilic part. Typically, Lutrol® F gels show increased viscosities when the temperature increases from room temperature to 40 °C.
Figure 2.7-1 Properties and structural formula of Lutrol® F 68 / micro 68 and Lutrol® F 127 / micro 127
Properties Ethylene oxide / propylene oxide
Different ratios Appearance Lutrol® F 68 / F 127
White, coarse-grained powders with a waxy consistency
Molecular weight Lutrol® F 68 / micro 68: ~ 8500 g / mol Lutrol® F 127 / micro 127: ~ 12000 g / mol
Solubility Lutrol® F 127 / micro 127 is soluble in water
and blends of alcohol and water, but is insoluble in diethyl ether, paraffi n wax and fatty oils
Lutrol® F 68 / micro 68 is freely soluble in water (opalescent solution) and ethanol, but is insoluble in diethyl ether, paraffi n and fatty oils
Lutrol® F 68 / micro 68:Methylene chloride approx. 35 %Chloroform approx. 40 %Acetonitrile approx. 20 %Acetone approx. 2 %Ethyl acetate approx. 1.5 %
Appearance Lµtrol® micro 68 / 127 White microprilled powders with a weak odor
2
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3110_P_0380_BASF_Buch_HotMelt_1_39.indd 31 27.10.2010 16:19:24 Uhr27.10.2010 16:19:24 Uhr
32
Pharmaceutical applications in addition to HME:Lutrol® F 68 is employed as an emulsifi er and solubilizer, also in drug formulations for parenteral use. Furthermore, it is used as a dispersing and wetting agent, to prepare solid dispersions and to improve the solubility, absorption and bioavailability of poorly soluble actives in solid oral dosage forms. The formulations are usually processed by melt granulation and spray granulation.
Lutrol® F 127 is used primarily as a thickening agent and gel former, but also as a co-emulsifi er and consistency enhancer in creams and liquid emulsions. It is also used as a solubilizer for certain active substances in pharmaceutical and cosmetic formulations.
Lµtrol® micro 68 and Lµtrol® micro 127 are poloxamers designed for direct compression,roller compaction, wet or melt granulation and hot-melt extrusion. This is because they have a much smaller particle size (approx. 50 µm) than the prilled grades, which renders them compatible with the particle sizes of actives and other excipients. Thus, these fi ne grades can be blended with drug mixtures without segregation, which is usually a risk when using the prilled Lutrol® grades. Their functionality is mainly for improving the wetting and dissolution of poorly soluble drugs. In addition they can also act as water-soluble lubricants in tablet formulation.
Intended use in HME:Poloxamers are intended to be used as plasticizers and as wetting and dissolution enhancers. Lµtrol® micro grades can be preblended with other components and also mix more homogeneously in the extruder.
2.8 Cremophor® RH 40
Cremophor® RH 40 (macrogolglycerol hydroxystearate 40) is a non-ionic solubilizer and emulsifying agent.
Figure 2.8-1 Properties of Cremophor® RH 40
Properties Cremophor® RH 40 consists of
Hydrophobic part: glycerol polyethylene glycol hydroxystearate, together with fatty acid glycerol polyglycol esters; Hydrophilic part: polyethylene glycols and glycerol ethoxylate
Appearance White to yellowish paste at 20 °C
Solubility Soluble in water, ethanol, 2-propanol, n-propanol, ethyl acetate,
chloroform, carbon tetrachloride, toluene, xylene
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3210_P_0380_BASF_Buch_HotMelt_1_39.indd 32 27.10.2010 16:19:24 Uhr27.10.2010 16:19:24 Uhr
H OO H
n
33
Pharmaceutical applications in addi-tion to HME:The main application is as a solubilizer and emulsifi er in oral and topical liquid and semi-solid dosage forms.
Properties Polyethylene glycols Appearance
Liquids or low-melting solids Molecular weight
~ 300 to ~ 10000000 g / mol Solubility
Polyethylene glycols are readily soluble in water, ethanol, acetone, glycols and chloroform
Figure 2.9-1 Properties and structural formula of PEG
Pharmaceutical applications in addi-tion to HME:PEGs of different molecular weights are used as co-solvents, plasticizers, thicke-ning agents and as matrix formers in oral, dermal and parenteral dosage forms.
Intended use in HME:Cremophor® RH 40 is intended to be used as plasticizer or solubility enhan-cer for actives that are poorly soluble in water.
2.9 Polyethylene Glycols
Polyethylene glycols (PEGs) are liquids or low-melting solids depending on their molecular weights. They are prepared by the polymerization of ethylene oxide and are commercially available with a wide range of molecular weights. The numbers that are often included in the names of PEGs indicate their average molecular weights, e.g. a PEG with n=9 would have an average molecular weight of approximately 400 g /mol and would be labeled PEG 400 (Lutrol® E 400).
Intended use in HME:The various PEGs are intended to be used as plasticizers.
2
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3310_P_0380_BASF_Buch_HotMelt_1_39.indd 33 27.10.2010 16:19:24 Uhr27.10.2010 16:19:24 Uhr
34
3 Physico-chemical Characteristics – Processability
Polymers for hot-melt extrusion must exhibit thermoplastic characteristics in order to make the hot-melt extrusion process possible and they must be thermally stable at the extrusion temperatures employed. Other relevant characteristics are: suitable glass transition and melting temperature (Tg or Tm) of 50 –180 °C, low hygroscopicity and no toxicity since larger amounts of polymer are used [26]. The extrudability of a polymer is mainly determined by Tg or Tm and melt viscosity [37]. Polymers with a high molecular weight exhibit high melt viscosity and are diffi cult to extrude. Moreover, a high Tg or Tm requires a high processing temperature which can cause degradation of sensitive actives [55]. As a general rule, an extrusion process should be run at tem-peratures 20 – 40 °C above the Tg. Most polymers demonstrate thixotropic behavior, which means that the viscosity reduces as a function of increasing shear stress.
3.1 Glass Transition Temperature and Melting Temperature
To determine the glass transition temperature and the melting points of the polymers, DSC-analysis was performed. These values should prove helpful in determining the lowest process temperatures to be used for the polymers in hot-melt extrusion.
Experimental method:Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 (TA Instrument, USA). DSC scans were recorded at a heating rate of 20 K / min in the second heating run.
Additional experimental parameters for measurements of pure polymers, plasticizers and polymer-plasticizer mixtures: All measurements were performed in a 2 bar pressurized pan except for Cremophor® RH 40 and Lutrol® F 127, which were tested in an open pan.
The drying conditions of polymers and plasticizers had to be adjusted for every single sample to ensure complete drying (drying above the Tg) without decomposition. The vacuum drying temperature varied from 140 °C to 200 °C.
Additional experimental parameters for measurements of polymer mixtures: The polymer blends were predried in open pans inside the DSC apparatus for ten minutes. The drying temperature varied from 160 °C to 200 °C.
3.1.1 DSC-Analysis of Pure Polymers and Plasticizers /Solubilizers
The glass transition temperature of PVP homopolymers increases from 90 °C to 156 °C as a function of molecular weight. The relatively low glass transition temperature of
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3410_P_0380_BASF_Buch_HotMelt_1_39.indd 34 27.10.2010 16:19:24 Uhr27.10.2010 16:19:24 Uhr
35
Kollidon® VA 64 is caused by the soft monomer vinyl acetate and in addition to that in the case of Soluplus® by the covalently bound PEG moiety. Soluplus® can be regarded as an internally plasticized molecule. The PEGs and poloxamers exhibit glass transition temperatures below freezing point; thus only the melting point is given here.
Figure 3.1.1-1 Glass transition temperatures and melting points of all tested BASF pharma polymers and plasticizers
Kolli
don
VA 6
4
Solu
plus
Kolli
don
12 P
F
Kolli
don
17 P
F
Kolli
don
30
Kolli
don
90 F
Kolli
don
SR
Kollic
oat M
AE 1
00P
Kolli
coat
IR
Kolli
coat
Pro
tect
Lutro
l F 1
27
PEG
1500
Lutro
l F 6
8
T g/T
m [°
C]
220
200
180
160
140
120
100
80
60
40
20
0
Tg [°C]Tm [°C]
101
70
90
138149 156 152
114
208 205
5745
55454539
3.1.2 DSC-Analysis of Polymer-Plasticizer Mixtures
DSC is also an excellent tool for studying the impact of plasticizers in polymers on glass transition temperature. For this reason, extrudates and cast fi lms consisting of polymer and plasticizer were analysed concerning their Tg.
Experimental methods:1. Polymer-plasticizer extrudates (Extrusion): The hot-melt extrusion of the polymer-plasticizer mixtures was performed using a twin-screw extruder ZSK 25 (Coperion Werner & Pfl eiderer, Germany) with a screw diameter of 25 mm and a length to diameter ratio of 34. Several extrusion parameters were varied: Loading of the extruder from 2.5 to 5 kg / h, extrusion temperature of 60 – 200 °C and the speed of the extruder screws from 100 to 150 rpm. The screw confi guration for all experiments was kept constant. After extrusion, the samples were cooled down on a conveyor belt and subsequently granulated.
2. Polymer-plasticizer fi lms (Film Casting): Polymer and plasticizer were dissolved in water and the solution casted using a Coatmaster (Erichsen Testing Equipment, Germany) using knives with different die gaps (150 – 500 m) and then dried at 40 °C.
3
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3510_P_0380_BASF_Buch_HotMelt_1_39.indd 35 27.10.2010 16:19:25 Uhr27.10.2010 16:19:25 Uhr
T g [°C
]
Kollidon VA64
Soluplus Kollidon 12PF
Kollidon 17PF
180
160
140
120
100
80
60
40
20
0
138
6771
9290
425047
70
54
83
103101
137
109102
Pure polymerLutrol F 68Cremophor RH 40PEG 1500
T g [°C
]
Kollidon 30 (*) Kollidon 90 F (*) Kollidon SR
180
160
140
120
100
80
60
40
20
0
152
128133
146156
118
101
129
149155
118
2532
18
39
Pure polymerLutrol F 68Cremophor RH 40PEG 1500
36
Figure 3.1.2-1 Tg of pure polymers in comparison to polymer-plasticizer combinations (extrudate, 9:1, w / w %)
Figure 3.1.2-2 Tg of pure polymers in comparison to polymer-plasticizer combinations (extrudate and fi lm (*), 9:1, w / w %), another color in the bar represents the presence of another Tg
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3610_P_0380_BASF_Buch_HotMelt_1_39.indd 36 27.10.2010 16:19:25 Uhr27.10.2010 16:19:25 Uhr
37
It is a well-known fact that the glass transition temperature can be reduced by the ad-dition of plasticizers. However, the additives tested acted in a different way. Whereas PEG 1500 and Cremophor® RH 40 decreased the glass transition temperatures in all systems signifi cantly, Lutrol® F 68 had no effect on several polymers. From these results, it can be concluded that PEG 1500 and Cremophor® RH 40 dissolve more homogeneously in most of the polymers tested than Lutrol® F 68.
3.1.3 DSC-Analysis of Polymer Mixtures
In these experiments, the extrudates of completely molten polymer mixtures were used as samples. If the polymers are completely miscible, only one Tg should occur. For an immiscible mixture, two glass transition temperatures (Tg signals of polymers) should be found. Similar principles also apply to the melting peaks of the crystalli-ne polymers. Partial miscibility would also result in two glass transition temperatures where at least one is shifted [56].
Matrix Polymer Kollidon® SR Kollicoat® IR Kollidon® 30 Kollidon® 90 F
Kollidon® VA 64 70:30 70:30 70:30 70:30
30:70 30:70 30:70 -
Soluplus® 70:30 70:30 70:30 70:30
30:70 30:70 30:70 -
Table 3.1.3-1 Tested polymer combinations (extrudates) by DSC-analysis
Experimental method:Preparation of the polymer mixtures by extrusion (Detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 4 – 5 kg / h Extrusion temperature: 120 – 200 °C Screw speed: 100 – 150 rpm
Kollidon® VA 64 and Soluplus® with Kollidon® SRDespite the fact that Kollidon® VA 64 and Kollidon® SR contain the same monomers but in a different polymer structure, they are obviously not miscible, since all glass transition temperatures remained almost the same. The slight increase of the Tg of Kollidon® VA 64 can be attributed to a lower water content of the extrudates or a partial mixing of the PVP contained in Kollidon® SR with Kollidon® VA 64.
3
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3710_P_0380_BASF_Buch_HotMelt_1_39.indd 37 27.10.2010 16:19:25 Uhr27.10.2010 16:19:25 Uhr
T g [°C
]
Kollidon VA 64 Soluplus
240
220
200
180
160
140
120
100
80
60
40
20
0
152160156
101
152161
7870
Pure polymerPolymer : Kollidon SR, 70:30Polymer : Kollidon SR, 30:70Kollidon SR
40
107 109
4339 38
41
86
39
38
The DSC curves of the Soluplus® – Kollidon® SR extrudates show a comparatively wide and unsharp peaks. However, partial miscibility is obvious since with 30 % Kol-lidon® SR, no PVP peak with a molecular weight of ~50.000 Dalton can be detected anymore. With larger quantities (70 % Kollidon® SR) the typical Tg of PVP of approx. 160 °C is still visible. Parallel to this, the Tg of Soluplus® increases.
Figure 3.1.3-1 Glass transition temperatures of the pure polymers and combinations of Kollidon® VA 64 and Soluplus® with Kollidon® SR (extrudates)
Kollidon® VA 64 and Soluplus® with Kollicoat® IRKollidon® VA 64 and Soluplus® in combination with Kollicoat® IR are not comple-tely miscible in the tested concentrations, as can be seen from the melting point of Kollicoat® IR. The decrease in glass transition temperature of Soluplus® and Kollidon® VA 64 in combination with Kollicoat® IR seems to be affected by the low Tg of this compound.
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3810_P_0380_BASF_Buch_HotMelt_1_39.indd 38 27.10.2010 16:19:26 Uhr27.10.2010 16:19:26 Uhr
T g/T m
* [°
C]
Kollidon VA 64 Soluplus
280
260
240
220
200
180
160
140
120
100
80
60
40
20
0
208**melting point
212*205*
101
208*215*212*
70
Pure polymerPolymer : Kollidon IR, 70:30Polymer : Kollidon IR, 30:70Kollicoat IR
88
5745
6151 45
39
Figure 3.1.3-2 Glass transition temperatures of the pure polymers and combinations of Kollidon® VA 64 and Soluplus® with Kollicoat® IR (extrudates)
Kollidon® VA 64 and Soluplus® with Kollidon® 30 and Kollidon® 90 FThe extrudates of Kollidon® VA 64 and Soluplus® with Kollidon® 30 and Kollidon® 90 F demonstrate that these polymers are not miscible by melting and homogenizing in a hot-melt extrusion process.
All experiments with Soluplus® and Kollidon® VA 64 in combination with PVP have shown that the glass transition temperatures of the used components remain almost unchanged. Slight variations in the glass transition temperature of the polymers can be explained by the different drying method used compared to the experiments with the pure polymers.
3
10_P_0380_BASF_Buch_HotMelt_1_39.indd 3910_P_0380_BASF_Buch_HotMelt_1_39.indd 39 27.10.2010 16:19:26 Uhr27.10.2010 16:19:26 Uhr
T g [°C
]
Kollidon VA 64 Soluplus
240
220
200
180
160
140
120
100
80
60
40
20
0
149151150
101
149
168171
70
Pure polymerPolymer : Kollidon 30, 70:30Polymer : Kollidon 30, 30:70Kollidon 30
110 112
76 78
T g [°C
]
Kollidon VA 64 Soluplus
240
220
200
180
160
140
120
100
80
60
40
20
0
156
177
101
156
177
70
not e
xtru
dabl
e
not e
xtru
dabl
e
Pure polymerPolymer : Kollidon 90 F, 70:30Polymer : Kollidon 90 F, 30:70Kollidon 90 F
107
77
40
Figure 3.1.3-3 Glass transition temperatures of the pure polymers and combinations of Kollidon® VA 64 and Soluplus® with Kollidon® 30 (extrudates)
Figure 3.1.3-4 Glass transition temperatures of the pure polymers and combinations of Kollidon® VA 64 and Soluplus® with Kollidon® 90 F (extrudates)
3.2 Melt Viscosity
Besides the glass transition temperature, the melt viscosity is another crucial factor determining extrudability.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4010_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:40 27.10.2010 16:11:49 Uhr27.10.2010 16:11:49 Uhr
Visc
osity
* [P
a s]
100000000
10000000
1000000
100000
10000
1000
1000.01 0.1 1 10 100
Angular frequency [rad/s]1000
Kollidon VA 64 (170 °C)Soluplus (170 °C)Kollidon 12 PF (130 °C)Kollidon 17 PF (180 °C)Kollidon 30 (190 °C)Kollidon 90 F (200 °C)Kollidon SR (170 °C)Kollicoat MAE 100P (150 °C)Kollicoat IR (180 °C)Kollicoat Protect (180 °C)
41
Figure 3.2.1-1 Melt viscosity of pure polymers as a function of angular frequency
Experimental method:Viscosity: Viscosity studies were performed using a shear stress-controlled rotational rheometer (SR5 Rheometrics, USA) at three different temperatures with a plate-to-plate measuring geometry (diameter of 25 mm, height of 1 mm).
3.2.1 Melt Viscosity of Pure Polymers
It is worthwhile obtaining these values in order to get some idea about the lowest process temperature to be used for the polymers in the hot-melt extrusion process. The infl uence of shear rate and temperature on the melt viscosity characteristics of the polymers was investigated.
Infl uence of shear rate on melt viscosityAll the polymers tested showed a decrease in dynamic melt viscosity with increasing angular frequency and shear rate respectively. Some of the tested polymers showed an unproportional increase in dynamic viscosity at higher temperatures and lower angular frequencies. This might well indicate an initiating cross-linking of the polymer chains. The infl uence of frequency/shear on the melt viscosity of the polymers is displayed for temperatures within the process temperature range of the pure polymers.
3
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4110_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:41 27.10.2010 16:11:49 Uhr27.10.2010 16:11:49 Uhr
Visc
osity
* [P
a s]
100
10
10.01 0.1 1 10 100
Angular frequency [rad/s]
- Lutrol F127 at 60 °C- Lutrol F127 at 70 °C- Lutrol F127 at 80 °C
42
Figure 3.2.1-2 Melt viscosity of Lutrol® F 127 as a function of the angular frequency at different temperatures
Infl uence of temperature on melt viscosityWith increasing temperature, the dynamic viscosity of all tested polymers decreased. Only Kollicoat® IR showed a slightly higher viscosity at 190 °C compared to the vis-cosity at 180 °C. This can probably be explained by an initiating cross-linking of the polymer chains. All the values presented in Figure 3.2.1-3 and 3.2.1-4 were determi-ned at 16 rad / s.
Melt viscosity is infl uenced by molecular weight and any interaction between the func-tional groups of the polymer chains. Thus, signifi cant differences between the various polymers were found. Melt viscosity increased strongly when going from Kollidon® 12 PF (~ 2500 Dalton) to Kollidon® 17 PF (~ 9000 Dalton), Kollidon® 30 (~ 50000 Dalton) and Kollidon® 90 F (1250000 Dalton). Despite a high molecular weight, Soluplus® (118000 Dalton) results in a similar viscosity to Kollidon® VA 64 (~ 55000 Dalton). For a small scale extruder, the limitation is at approximately 10000 Pa*s since higher vis-cosities generate too much torque. On the other hand, the polymer should not exhibit a very low viscosity because of problematic downstream processing.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4210_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:42 27.10.2010 16:11:49 Uhr27.10.2010 16:11:49 Uhr
Visc
osity
* [P
a s]
1000000
100000
10000
1000
100
10120 140
Temperature [°C]160 180 200 220 240
Optimalmeltviscosityrange forHME
Kollidon VA 64SoluplusKollidon 12 PFKollidon 17 PFKollidon 30Kollidon 90 FKollidon SRKollicoat MAE 100PKollicoat IRKollicoat Protect
Visc
osity
* [P
a s]
1000000
100000
10000
1000
100
10
150 60
Temperature [°C]70 80 90 100 110
Optimalmeltviscosityrange forHME
Lutrol F 127
43
Figure 3.2.1-3 Melt viscosity of pure polymers as a function of temperature
Figure 3.2.1-4 Melt viscosity of Lutrol® F 127 as a function of temperature
3
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4310_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:43 27.10.2010 16:11:49 Uhr27.10.2010 16:11:49 Uhr
Visc
osity
* [P
a s]
10000
1000
100
10140 150 160 170 180 190 200 210
Temperature [°C]
Kollidon VA 64Kollidon VA 64 / Lutrol F 68 (4:1)Kollidon VA 64 / Cremophor RH 40 (4:1)Kollidon VA 64 / PEG 1500 (4:1)
44
Figure 3.2.2-1 Infl uence of different plasticizers on the melt viscosity of Kollidon® VA 64
3.2.2 Infl uence of Plasticizers on Melt Viscosity
Sometimes melt viscosities have to be lowered in order to be able to run a smoother process. This can be achieved by adding plasticizers. We recommend not using liquid plasticizers but solid or at least semi-solid ones since their diffusivity in the matrix is li-mited; this leads to better stability. Cremophor® RH 40, Lutrol® F 68 and PEG 1500 are all effective in reducing viscosity, the most pronounced effect being with Lutrol® F 68.All the values presented in Figure 3.2.2-1 were determined at 16 rad / s.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4410_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:44 27.10.2010 16:11:50 Uhr27.10.2010 16:11:50 Uhr
100
Mass Change: -56.1%
Mass Change: -24.1%Mass Change: -2.5%
Start of decompositionLoss of water
150 200 250 300 350 400 450
Mas
s [%
]
100
90
80
70
60
50
40
30
20
50
Temperature/°C
[1]+
+
45
Figure 3.3-1 TGA diagram example of Soluplus®
3.3 Decomposition by TGA
In principle, all organic materials can be degraded by increasing temperature. Thermal gravimetric analysis (TGA) is a suitable tool for examining the thermal sensitivity of a polymer. At least at the extrusion temperature, which is usually between 100 °C and 200 °C, it must be stable. Even if this method is not capable of delivering detailed information about cross-linking of the polymer chains and a few other possible reac-tions, it provides at least an idea about the changes that take place upon heating. Thus, changes in the mass with increasing temperature and the kind of reactions (endothermic or exothermic) can be determined. One more thing which has to be considered, is the time during which the material is exposed to the temperature. Long heat exposure might lead to decomposition, while the material is stable for a shorter time at the same temperature. Exemplarily, a TGA diagram of Soluplus® is shown in Figure 3.3-1.
Experimental method:Thermo gravimetric analyses (TGA): TGA were performed using a Netzsch STA 409 C / CD instrument (USA). TGA scans were recorded at a heating rate of 5 K / min until 450 °C (air atmosphere).
3
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4510_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:45 27.10.2010 16:11:50 Uhr27.10.2010 16:11:50 Uhr
Tem
pera
ture
[°C]
300
250
200
150
100
50
0
230
101
Kolli
don
VA 6
4
Solu
plus
Kolli
don
12 P
F
Kolli
don
17 P
F
Kolli
don
30
Kolli
don
90 F
Kolli
don
SR
Kolli
coat
MAE
100
P
Kolli
coat
IR*
Kolli
coat
Pro
tect
*
Lutro
l F12
7*
250
70
225
90
175
138
175
149
200
156
210
152
39
150
114
200208*
200205*
180
55*45 45
Tg (or *Tm)T(degradation)
46
Figure 3.3.1-1 Comparison of Tg or Tm (by DSC) with T(degradation) (by TGA) ofpure polymers
3.3.1 TGA of Polymers
The difference between glass transition temperatures (Tg) or melting temperature (Tm) and T(degradation) serves as an indication of the extrusion range, which is defi ned as the temperature range within which extrusion can be performed from a process and stability point of view. The broadest range by far was found with Soluplus®, followed by Kollidon® VA 64, Kollidon® 12 PF and Lutrol® F 127. Materials with a high Tg can only be extruded within a small, relatively high temperature range.
3.3.2 TGA of Plasticizers
Since plasticizers are often included in formulations for extrusion, they also must be stable at high temperatures. Based on the results obtained, PEG 1500 can be used at up to 175 °C, Lutrol® F 68 at up to 180 °C and Cremophor® RH 40 at up to 200 °C.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4610_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:46 27.10.2010 16:11:50 Uhr27.10.2010 16:11:50 Uhr
Tem
pera
ture
[°C]
250
200
150
100
50
0
180
55
Lutro
l F 6
8
Crem
opho
r RH
40
PEG
1500
Whi
te to
yel
low
ish
past
e at
20
°C
175
45
200
Tm
T(degradation)
47
Figure 3.3.2-1 Comparison of Tm (by DSC) with T(degradation) (by TGA) of pure plasticizers
3.3.3 TGA of Active Pharmaceutical Ingredients
The TGA results of the three model drugs fenofi brate, carbamazepine and itraco-nazole indicate that these can be extruded at temperatures up to at least 180 °C. Of course, for a detailed investigation, HPLC analysis should be performed.
3
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4710_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:47 27.10.2010 16:11:50 Uhr27.10.2010 16:11:50 Uhr
Tem
pera
ture
[°C]
350
300
250
200
150
100
50
0
Feno
fibra
te
Carb
amaz
epin
e
Itrac
onaz
ole
275
166.2180
80-81
220190-193
Tm
T(degradation)
48
Figure 3.3.3-1 Comparison of Tm with T(degradation) (by TGA) of active pharmaceutical ingredients
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4810_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:48 27.10.2010 16:11:50 Uhr27.10.2010 16:11:50 Uhr
49
Table 3.4-1 Compilation of the specifi c heat capacity of the tested polymers at 25.0 °C, 100.0 °C and 175.0 °C
3.4 Specifi c Heat Capacity of Pure Polymers
The specifi c heat capacity is the amount of heat that must be added (or removed) from a unit mass of a substance to change its temperature by one degree Kelvin.
This was determined by DSC-experiments and is helpful in designing the screw con-fi guration for the extrusion of the polymer. The higher the specifi c heat capacity, the more energy has to be generated and transferred into the polymer to melt it. Princi-pally, such a polymer requires a more aggressive screw confi guration.
Experimental method:Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 TA Instrument (USA). DSC scans were recorded at a heating rate of 20 K /min in the second heating run.
Samplecp (25.0 °C)[J / gK]
cp (100.0 °C)[J / gK]
cp (175.0 °C)[J / gK]
Kollidon® VA 64 1.228 1.634 2.137
Soluplus® 1.396 1.937 2.100 (145 °C)
Kollidon® 12 PF 1.263 1.740 2.170
Kollidon® 17 PF 1.205 1.508 2.061
Kollidon® 30 1.235 1.573 2.142
Kollidon® 90 F 1.233 1.563 2.142
Kollidon® SR 1.270 1.857 2.073
Kollicoat® MAE 100P 1.298 1.694 2.149 (150 °C)
Kollicoat® IR 1.880 2.340 3.046
Kollicoat® Protect 1.703 2.487 3.668
Lutrol® F 127 1.809 2.111 x
The polymers tested showed specifi c heat capacities in a range of 1.5 to 2.5 J / gK. The highest values were found for Kollicoat® IR and Kollicoat® Protect. For processing these polymers more energy has to be transferred in the hot-melt extrusion process.
3
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:4910_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:49 27.10.2010 16:11:51 Uhr27.10.2010 16:11:51 Uhr
c p [J
/gK]
3.000
2.000
1.000
0.000
Kolli
don
VA 6
4
Solu
plus
Kolli
don
12 P
F
Kolli
don
17 P
F
Kolli
don
30
Kolli
don
90 F
Kolli
don
SR
Kolli
coat
MAE
100
P
Kolli
coat
IR
Kolli
coat
Pro
tect
Lutro
l F12
7
50
Figure 3.4-1 Compilation of the specifi c heat capacity (cp) of the polymers at 100 °C
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5010_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:50 27.10.2010 16:11:51 Uhr27.10.2010 16:11:51 Uhr
H2O
Active(excess)
Polymer(10 w%)
72 h stirring,room temperature
UV detectionof solubilized active
UV
Filtration
51
Figure 3.5-1 Solubilization setup
3.5 API Solubility Enhancement of Pure Polymers
A potential affi nity between polymers and a drug that is poorly soluble in water can be pretested using various methods. The solubilization capacity of the different polymers can be tested by determining the saturation solubility of such a poorly soluble drug in a polymer solution. Using phosphate buffer as a solvent (e.g. pH 7.0) ensures com-parable conditions when testing ionic solubilizers or drugs. Thus, solubility effects due to pH shifts can be avoided.
Experimental method:Solubilization procedure: A 10 % polymer solution in phosphate buffer is oversa-turated with a discrete drug and stirred for 72 h at room temperature. The resulting suspension is fi ltered through 0.45 µm fi lter and the content of solubilized drug is determined in the fi ltrate by UV spectroscopy with the 8453 UV-Visible spectropho-tometer (Agilent, USA).
Preparation of saturated solution of drug in 10 % polymer solution 72 h stirring (room temperature) and fi ltration (0.45 µm fi lter) Determination of dissolved amount of drug by UV / Vis
The following fi gures show the results of the solubility enhancement of different poly-mers and PEG 1500 as a plasticizer for various water-insoluble drugs in comparison with the API solubilities in phosphate buffer at pH 7.0. Soluplus® outperformed by far all other polymers and resulted in an enhancement of the saturation solubility for all tested drugs. From these results it is obvious that Soluplus® is capable of effectively solubilizing these water-insoluble drugs. Higher solubilities were achieved only in the case of piroxicam with other polymers, in particular for Kollidon® VA 64; this was caused by a specifi c complexation of this drug with the vinylpyrrolidone and vinyl acetate moiety.
In contrast, Soluplus® increases drug solubility mainly by forming micelles, which can take up lipophilic drugs almost independently of their structures.
3
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5110_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:51 27.10.2010 16:11:51 Uhr27.10.2010 16:11:51 Uhr
Estra
diol
Pirox
icam
Clotrim
azole
Carbam
azep
ine
Griseo
fulvin
Ketoc
onaz
ole
Cinnari
zine
Feno
fibrat
e
Itraco
nazo
le
Danaz
ol
Satu
ratio
n so
lubi
lity
[g/1
00m
L]
0.60
0.50
0.40
0.30
0.20
0.10
0.00 ~0.
001
~0.
001
~0.
001~
0.08
0
~0.
001
~0.
013
~0.
0001
~0.
0001
~0.
0001
~0.
026
* ** * * * ** *
0.55
0.45
0.35
0.25
0.15
0.05
*No improvement of solubility
Kollidon VA 64SoluplusKollidon 17 PFPure API
Estra
diol
Pirox
icam
Clotrim
azole
Carbam
azep
ine
Griseo
fulvin
Ketoc
onaz
ole
Cinnari
zine
Feno
fibrat
e
Itraco
nazo
le
Danaz
ol
Satu
ratio
n so
lubi
lity
[g/1
00m
L]
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0.55
0.45
0.35
0.25
0.15
0.05
~0.
001
~0.
001
~0.
001~
0.08
0
~0.
001
~0.
013
~0.
0001
~0.
0001
~0.
0001
~0.
026
* * * * * * * * * * *
*No improvement of solubility
Kollidon SRKollicoat IRPEG 1500Pure API
52
Figure 3.5-2 Solubility enhancement of Kollidon® VA 64, Soluplus® and Kollidon® 17 PF for various drugs in comparison to the API solubilities in phosphate buffer at pH 7.0
Figure 3.5-3 Solubility enhancement of Kollidon® SR, Kollicoat® IR and PEG 1500 for various drugs in comparison to the API solubilities in phosphate buffer at pH 7.0
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5210_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:52 27.10.2010 16:11:52 Uhr27.10.2010 16:11:52 Uhr
53
3.6 Calculation of Solubility Parameters of Pure Polymers, Plasticizers and APIs
The computer program SPWin (version 2.1) was used for calculation of the threedi-mensional solubility parameters for polar systems according to Hansen [57]. This pro-gram contains an advanced parameter set based on the group contribution methods of Fedors [58] and Van Krevelen and Hoftyzer [59]. Group contribution by Fedors and Van Krevelen and Hoftyzer were combined by Braun and Gröning [60] and were mo-difi ed and optimized by Breitkreutz for the software SPWin 2.1.
For the calculation the structures of the polymers, plasticizers and drugs have to be divided into functional groups, whereby each atom may only occur once. The deter-mining factor for the affi liation to a group is its priority in chemical nomenclature. The solubility parameters of polymers and plasticizers are always related to an approxima-te molecular weight given in chapter 2 – General Notes on BASF Pharma Polymers. The number of groups can be determined from the molecular weight of the polymer or plasticizer and the structure of the monomer. For Cremophor® RH 40 containing different structures, the calculation of the solubility parameter did not make much sense [61].
Solubility parameters were defi ned as: δd dispersion components
Components of intermolecular dispersion or Van der Waals forces
i Structural group within the molecule Fd Group contributions to dispersion forces Vi Group contributions to molar volume
δp polar components Components of intermolecular polar forces
i Structural group within the molecule Fp Group contributions to polar forces Vi Group contributions to molar volume
δh hydrogen bonding components Components of intermolecular hydrogen bonding
i Structural group within the molecule Eh Group contributions to hydrogen bond energy Vi Group contributions to molar volume
3
δp = ∑ Fpi
i
∑ Vii
2
δh = ∑ Ehi
∑ Vi
i
i
δd = ∑ Fdi
i
∑ Vii
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5310_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:53 27.10.2010 16:11:52 Uhr27.10.2010 16:11:52 Uhr
54
δv calculation of the combined solubility parameters δd and δp
δtotal calculation of the combined solubility parameters δd, δp and δh
The calculated solubility parameter can be used as an initial tool to predict the mis-cibility of compounds. Agents with similar δ values are expected to be miscible. The polymers and plasticizers show quite similar δd, δp, δh,δv and (δtotal) solubility parame-ters (except Kollicoat® IR). The parameters for the APIs display compliance between fenofi brate and itraconazole and a higher deviation for carbamazepine.
Table 3.6-1 Three-dimensional (δd, δp, δh), combined (δv) and total (δtotal) solubility parameters of different polymers
Polymerδd
[MPa0.5]δp
[MPa0.5]δh
[MPa0.5]δv
[MPa0.5]δtotal
[MPa0.5]
Kollidon® VA 64 17.4 0.5 9.2 17.4 19.7
Soluplus® 17.4 0.3 8.6 17.4 19.4
Kollidon® 12 PF 17.3 2.4 8.5 17.5 19.4
Kollidon® 17 PF 17.4 1.3 8.6 17.5 19.4
Kollidon® 30 17.4 0.6 8.6 17.4 19.4
Kollidon® 90 F 17.4 0.1 8.6 17.4 19.4
Kollidon® SR 17.4 0.1 10.2 17.4 20.2
Kollicoat® MAE 100P* 18.3 0.1 11.1 18.3 21.4
Kollicoat® IR 20.8 0.6 24.9 20.8 32.5
Kollicoat® Protect 21.3 0.6 26.5 21.3 34.0
Lutrol® F 127 17.6 0.8 9.5 17.7 20.1
* Calculated for the acid form
δv = δd + δp2 2
δtotal = δd + δp + δh2 2 2
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5410_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:54 27.10.2010 16:11:52 Uhr27.10.2010 16:11:52 Uhr
55
Table 3.6-2 Three-dimensional (δd, δp, δh), combined (δv) and total (δtotal) solubility parameters of different plasticizers
Table 3.6-3 Three-dimensional (δd, δp, δh), combined (δv) and total (δtotal) solubility parameters of different APIs
Plasticizerδd
[MPa0.5]δp
[MPa0.5]δh
[MPa0.5]δv
[MPa0.5]δtotal
[MPa0.5]
Lutrol® F 68 17.8 1.0 9.8 17.8 20.3
PEG 1500 18.0 2.5 11.2 18.2 21.4
APIδd
[MPa0.5]δp
[MPa0.5]δh
[MPa0.5]δv
[MPa0.5]δtotal
[MPa0.5]
Fenofi brate 19.8 4.2 6.7 20.3 21.4
Carbamazepine 23.7 8.0 10.2 25.0 27.0
Itraconazole 19.4 5.4 10.3 20.1 22.6
3
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5510_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:55 27.10.2010 16:11:53 Uhr27.10.2010 16:11:53 Uhr
56
4 Design of Extrusion Experiments
The hot-melt extrusion technique was used to process BASF pharma polymers in the absence and presence of different plasticizers. Moreover, different blends were also produced using combinations of some of these polymers. This chapter mainly provides detailed information on the hot-melt extrusion set up, experimental proce-dure, processing conditions, effect of plasticizers on processing of the polymers and handling of the extruded products.
4.1 Extrusion of Pure Polymers
The following pure BASF pharma polymers were investigated:Kollidon® VA 64Soluplus®
Kollidon® 12 PF Kollidon® 17 PFKollidon® 30Kollidon® 90 FKollidon® SR Kollicoat® MAE 100PKollicoat® IRKollicoat® ProtectLutrol® F 127
4.1.1 Extrusion Temperature Range of Pure Polymers
The polymers were processed at different temperatures in a co-rotating twin-screw extruder. The temperature range selected was the lowest possible processing tempe-rature to the highest. The lowest temperature was determined by various factors such as Tg or Tm, the melt viscosity, the power consumption of the twin-screw extruders (by means of Ampere) and the pressure in the extruder. The highest possible processing temperature was determined by the thermal stability of the polymers.
Experimental method:Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 2 to 5 kg / h Extrusion temperature: 60 – 200 °C Screw speed: 100 – 150 rpm
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5610_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:56 27.10.2010 16:11:53 Uhr27.10.2010 16:11:53 Uhr
Kollidon VA 64
Temperature [°C]
Kollidon 12 PF
Kollidon 17 PF
Kollidon SR
Kollicoat IR
KollicoatProtect
Lutrol F 127 – above 60 °C low viscous liquids –
Soluplus
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240
57
Taking the Tg or Tm (by DSC), the melt viscosity and the T(degradation) (indicated by start of mass reduction by TGA or discoloration) and the determination of the lowest and highest processing temperatures by hot-melt extrusion into consideration, Kollidon® VA 64, Soluplus®, Kollidon® 12 PF and Lutrol® F 127 demonstrated excellent suitabi-lity for extrusion. Kollidon® 17 PF, Kollidon® SR, Kollicoat® IR and Kollicoat® Protect were diffi cult to extrude because of a higher Tg or Tm, melt viscosities and the smaller difference of T(degradation) to Tg. Povidones of higher molecular weight (Kollidon® 30 and Kollidon® 90 F) and Kollicoat® MAE 100P as pure polymers were not processed by HME due to their degradation.
Figure 4.1.1-1 Temperature ranges for the extrusion of pure polymers
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5710_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:57 27.10.2010 16:11:53 Uhr27.10.2010 16:11:53 Uhr
58
4.1.2 Appearance and Pelletizing Characteristics of Extrudates
Appearance and pelletizing behavior of the extrudates are important characteristics from the product and process point of view.
Appearance of Kollidon® VA 64The extrudates of Kollidon® VA 64 look quite clear, glassy and regular. With increasing extrusion temperature the color turns yellowish and brownish. Above 220 °C extru-sion temperature, pelletizing – under the set extrusion conditions – becomes quite diffi cult.
Figure 4.1.2-1 Extrudate of Kollidon® VA 64
Figure 4.1.2-2 Extrudate of Soluplus®
160 °C
160 °C
180 °C
180 °C
220 °C
200 °C
240 °C
220 °C
Appearance of Soluplus®
Soluplus® also appears clear, glassy and regular as an extrudate at low temperatures. Above 200 °C, the color changes slowly into yellowish / golden.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5810_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:58 27.10.2010 16:11:53 Uhr27.10.2010 16:11:53 Uhr
59
Figure 4.1.2-3 Extrudate of Kollidon® 12 PF
Figure 4.1.2-4 Extru-date of Kollidon® 17 PF
Figure 4.1.2-5 Extrudate of Kollidon® SR
100 °C
175 °C
170 °C
130 °C
180 °C
150 °C
200 °C
Appearance of Kollidon® 12 PFThe extrudates of Kollidon® 12 PF are quite clear and brittle; this leads to a wide par-ticle size distribution and irregular shapes.
Appearance of Kollidon® 17 PFThe extrudate of Kollidon® 17 PF appears quite clear and brittle; this leads to a wide particle size distribution and irregular shapes.
Appearance of Kollidon® SRExtrudates of Kollidon® SR are yellowish opaque. Kollidon® SR remains fl exible for a comparatively long time (after leaving the extruder). For this reason, pelletizing of the strands of pure polymer is challenging.
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:5910_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:59 27.10.2010 16:11:55 Uhr27.10.2010 16:11:55 Uhr
60
Figure 4.1.2-6 Extru-date of Kollicoat® IR
Figure 4.1.2-7 Extru-date of Kollicoat® Protect
160 °C
160 °C
Appearance of Kollicoat® IRThe extrudate of Kollicoat® IR looks quite clear and re-gular. With increasing extrusion temperature, the color becomes slightly darker. However, Kollicoat® IR extru-dates processed at temperatures of 160 °C are no lon-ger completely water-soluble.
Appearance of Kollicoat® ProtectThe extrudate appears quite clear to cloudy and re-gular. With increasing extrusion temperature, the color becomes slightly darker. However, Kollicoat® Protect extrudates processed at temperatures of 160 °C are no longer completely water-soluble.
Figure 4.1.2-8 Extrudate of Lutrol® F 127
60 °C 100 °C 200 °C
Appearance of Lutrol® F 127Lutrol® F 127 melts at a comparatively low temperature and shows an extremely low viscosity already around 60 °C, so that cooling and pelletizing is a challenge. The extrudate of Lutrol® F 127 is white.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6010_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:60 27.10.2010 16:11:56 Uhr27.10.2010 16:11:56 Uhr
61
PolymerProcessing Temperature [°C]
Characteristics Pure Polymer
Kollidon® VA 64 150 Appearance: Clear
Pelletizing: + (Regular pellets)
Soluplus® 120 Appearance: Clear
Pelletizing: + (Regular pellets)
Kollidon® 12 PF 100 Appearance: Quite clear
Pelletizing: + (Irregular pellets, brittle extrudates)
Kollidon® 17 PF 175 Appearance: Quite clear
Pelletizing: o (Brittle extrudate)
Kollidon® SR 135 Appearance: Opaque, slight yellowish
Pelletizing: + (Regular pellets)
Kollicoat® IR 160 Appearance: Quite clear
Pelletizing: + (Regular pellets)
Kollicoat® Protect 160 Appearance: Quite clear to cloudy
Pelletizing: + (Regular pellets)
Lutrol® F 127 60 Appearance: White
Pelletizing: - (> 60 °C low viscose liquid)
Table 4.1.2.-1 Overview of the appearance and pelletizing behavior of pure polymer extrudates
Soluplus® and Kollidon® VA 64 extrudates have a clear appearance and show good pelletizing behavior. Fairly good results for pelletizing were achieved with Kollicoat® IR, Kollicoat® Protect and Kollidon® SR. Within the range of PVP polymers, Kollidon® 12 PF demonstrated better pelletizing behavior than Kollidon® 17 PF although both poly-mers have a tendency to create brittle extrudates. The pelletizing of Lutrol® F 127 was impossible because of the low viscosity of the extrudate at 60 °C.
4
+ Good pelletizing behavioro Poor pelletizing behavior- Pelletizing is impossible
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6110_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:61 27.10.2010 16:11:57 Uhr27.10.2010 16:11:57 Uhr
62
4.1.3 Dissolution Characteristics of Polymer Extrudates
In order to determine the dissolution characteristics of the extrudates, dissolution experiments in different media were performed.
Experimental method:Dissolution: These were conducted in a USP-conform dissolution apparatus with 900 mL volume at 100 rpm. The cylindrical extrudates of approximately 2 cm length and a diameter of 4 mm were tested in several buffer media with different pH-values (1.1, 6.8 and 9.0).
Table 4.1.3-1 Dissolution time of tested extrudates in a USP-conform dissolution apparatus
Sample
Extrusion temperature
Dissolution time [h:min]
[°C] pH-value 1.1 pH-value 6.8 pH-value 9.0
Kollidon® VA 64 180 00:17 00:21 00:19
Soluplus® 145 01:15 01:35 01:43
Kollidon® 12 PF 130 00:04 00:06 00:08
Kollidon® 17 PF 175 00:08 00:06 00:09
Kollidon® SR 180 >24:00 >24:00 >24:00
Kollicoat® IR 160 >24:00 >24:00 >24:00
Kollicoat® Protect 160 >24:00 >24:00 >24:00
Lutrol® F 127 100 01:01 00:30 01:12
Kollidon® VA 64, Soluplus® , Kollidon® 12 PF, Kollidon® 17 PF and Lutrol® F 127 dissolved completely in aqueous media of various pH within a short period of time. As expected, Kollidon® SR extrudates did not dissolve since they contained polyvinyl acetate as a water-insoluble polymer. Surprisingly, Kollicoat® IR and Kollicoat® Protect, as water-soluble polymers, also did not dissolve completely. This effect might be a result of a cross-linking reaction caused by the high extrusion temperatures. Other experiments with Kollicoat® IR in combination with plasticizer and at lower extrusion temperature showed complete dissolution in aqueous media.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6210_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:62 27.10.2010 16:11:58 Uhr27.10.2010 16:11:58 Uhr
w(lo
g(M
))
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.001,000 10,000 100,000
Kollidon VA 64 LOT 76964875L0extruded 160 °C
Kollidon VA 64 LOT 76964875L0
1,000,000 10,000,000
M/Da
63
Figure 4.1.4-1 Molecular weight distribution curves of Kollidon® VA 64 (powder) and Kollidon® VA 64 (extrudate)
4.1.4 Decomposition of Polymers during Extrusion
In addition to TGA analysis, GPC (Gel Permeation Chromatography) of Kollidon® VA 64 and Soluplus® was performed. The GPC was conducted in order to capture cross-linking or split of the polymer chains. Additionally, chemical test parameters according to the Certifi cate of Analysis were performed to study the stability of Kollidon® VA 64 and Soluplus® in the hot-melt extrusion process.
Kollidon® VA 64As the curves show, there was no change in molecular weight distribution after ext-rusion at 160 °C.
Furthermore, the chemical parameters reveal no signifi cant difference; in particular no saponifi cation of the ester group could be determined. Backsplit of the polymer chain into monomers was also not observed.
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6310_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:63 27.10.2010 16:11:58 Uhr27.10.2010 16:11:58 Uhr
64
Figure 4.1.4-2 Stability of Kollidon® VA 64 during extrusion at 160 °C
Test parameter
Vinyl acetate [mg / kg]
Vinyl pyrrolidone [mg / kg]
Acetaldehyde [mg / kg]
Peroxide [mg / kg]
2-Pyrrolidone [g / 100g]
Saponifi cation value [mg KOH / g]
pH-value (10 % in solution)
K-value (1 % aqueous solution)
Requirements
max. 10 <10 <10
max. 10 <2 <2
max. 500 <10 <10
max. 400 <20 <20
0,5 0.06 0.06
230 – 270 246 237
min. 3.0 max. 7.0
4.1 4.1
min. 25.2 max. 30.8
27.0 26.6
Results powder Results extrudate
Soluplus®
Comparable to Kollidon® VA 64, Soluplus® also showed no degradation. The mole-cular weight remained constant, as did the chemical parameters. A split of the ester or the caprolactam from the polymer chain would have led to lower ester and pH-values, higher acetic acid values and higher caprolactam concentrations.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6410_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:64 27.10.2010 16:11:58 Uhr27.10.2010 16:11:58 Uhr
65
Figure 4.1.4-3 Stability of Soluplus® during extrusion at 140 °C and 180 °C
Test parameter
Identifi cation (IR)
pH-value
Ester value [mg KOH / g]
Vinyl acetate [ppm]
Vinyl caprolactam [ppm]
Caprolactam [g / 100g]
Ethylenglykole [ppm]
Acetic acid / Acetate [ppm]
Peroxide [ppm]
Molecular weight Mw [g / mol]
Powder
conforms conforms conforms
4.1 3.9 3.9
197 196 196
<2 <2 <2
<10 <10 <10
0.3 0.3 0.3
<100 60 63
365
<20
118,000
399
<20
119,000
396
<20
116,000
Extrudate [extruded at 140 °C]
Extrudate [extruded at 180 °C]
No change in chemical and physico-chemical parameters up to 180 °C
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6510_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:65 27.10.2010 16:11:59 Uhr27.10.2010 16:11:59 Uhr
66
4.2 Extrusion of Polymer-Plasticizer Combinations
The specifi c objective was to investigate the effect of various plasticizers on the processing temperature of different polymers.
Polymers: Plasticizers:Kollidon® VA 64 Lutrol® F 68Soluplus® Cremophor® RH 40Kollidon® 12 PF PEG 1500Kollidon® 17 PFKollidon® SRKollicoat® IRKollicoat® Protect
4.2.1 Extrusion Temperature Range of Polymer-Plasticizer Combinations
Three plasticizers – Lutrol® F 68, Cremophor® RH 40 and PEG 1500 – were investi-gated. In general, it was found that 10 % (w / w) of the plasticizers were suffi cient for a signifi cant decrease in extrusion temperatures. Lutrol® F 68 and PEG 1500 could be added in powder form using a separate powder feeder. Cremophor® RH 40 was added in molten form using a melt pump. The temperature range for extrusion was determined according to the method employed for the pure polymers.
Experimental method:Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 2.5 to 5 kg / h Extrusion temperature: 60 – 200 °C Screw speed: 100 – 150 rpm
It is obvious that all the polymer-plasticizer combinations could be processed below the processing temperatures of the pure polymers; however, this reduction was not the same for all the polymers. The highest reduction of 50 °C was observed for Kol-lidon® SR with all three plasticizers. This is in line with previous studies on the plasti-cizing effects in fi lm coatings based on polyvinyl acetate, where small amounts also showed a tremendous effect.
The type of plasticizer also had a signifi cant impact since PEG 1500 decreased the extrusion temperatures more than the others. This can probably be attributed to the low molecular weight of this plasticizer.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6610_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:66 27.10.2010 16:11:59 Uhr27.10.2010 16:11:59 Uhr
Kollidon VA 64
Temperature [°C]
Kollidon 12 PF
Kollidon 17 PF
Kollidon SR
Kollicoat IRNo effect of plasticizer *
No effect of plasticizer * KollicoatProtect
Soluplus
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240
Pure Polymer
+ 10% Lutrol F 68
Kollidon VA 64
Temperature [°C]
Kollidon 12 PF
Kollidon 17 PF
Kollidon SR
Kollicoat IRNo effect of plasticizer *
No effect of plasticizer * KollicoatProtect
Soluplus
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240
Pure Polymer
+ 10% Cremophor RH 40
67
Figure 4.2.1-1 Temperature range for extrusion of polymer / Lutrol® F 68 combinations (9:1, w / w %)
Figure 4.2.1-2 Temperature range for extrusion of polymer / Cremophor® RH 40 combinations (9:1, w / w %)
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6710_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:67 27.10.2010 16:11:59 Uhr27.10.2010 16:11:59 Uhr
Kollidon VA 64
Temperature [°C]
Kollidon 12 PF
Kollidon 17 PF
Kollidon SR
Kollicoat IR
KollicoatProtect
Soluplus
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240
Pure Polymer
+ 10% PEG 1500
68
Figure 4.2.1-3 Temperature range for extrusion of polymer / PEG 1500 combinations (9:1, w / w %)
4.2.2 Appearance and Pelletizing Characteristics of Polymer-Plasticizer Extrudates
The appearance of the polymer-plasticizer extrudates and pelletizing behavior are im-portant characteristics, particularly for downstream processing. The type of plasticizer had a signifi cant impact since PEG 1500 only slightly deteriorated the appearance and pelletizing behavior of the polymer-plasticizer extrudates compared to the extru-dates of pure polymer. More deviation of appearance and pelletizing was observed for Lutrol® F 68, the strongest deviation being observed for Cremophor® RH 40. In general, the addition of plasticizers made pelletizing more diffi cult. Quite often, appea-rance changed from clear to opaque.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6810_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:68 27.10.2010 16:11:59 Uhr27.10.2010 16:11:59 Uhr
69
+ Good pelletizing behavioro Poor pelletizing behavior
Table 4.2.2-1 Overview of appearance and pelletizing behavior of different extrudates in the presence of plasticizers (ratio polymer to plasticizer 9:1, w / w %)
Polymer Characteristics
Plasticizer 10 % (w / w %)
Lutrol® F 68Cremophor® RH 40
PEG 1500
Kollidon® VA 64
Appearance: Opaque Opaque Clear
Pelletizing:+ (150 °C)(Irregular pellets)
+ (150 °C)(Irregular pellets)
+ (150 °C)(Irregular pellets)
o (135 °C) o (125 °C) o (125 °C)
Soluplus®
Appearance: Clear Clear Clear
Pelletizing:
+ (120 °C)(Regular pellets)
o (120 °C) o (120 °C)
o (100 °C) o (100 °C) + (90 °C)(Irregular pellets)
Kollidon® 12 PFAppearance: Opaque Opaque Almost clear
Pelletizing: o (60+100 °C) o (60+100 °C) o (60+100 °C)
Kollidon® 17 PF
Appearance: Opaque Opaque Clear
Pelletizing: o (165+175 °C)(Brittle extrudate)
o (165+175 °C)(Brittle extrudate)
o (145+175 °C)(Brittle extrudate)
Kollidon® SR
Appearance: Opaque(Yellowish)
Opaque(Yellowish)
Opaque(Yellowish)
Pelletizing:
+ (135 °C)(Regular pellets)
o (135 °C) + (135 °C)(Regular pellets, stick together)
o (85 °C) o (85 °C) o (85 °C)
Kollicoat® IRAppearance: Opaque Opaque Almost clear
Pelletizing: o (160 °C) o (160 °C) + (140 °C) (Irregular pellets)
Kollicoat® Protect
Appearance: Opaque Opaque Almost clear
Pelletizing:
+ (160+180 °C)(Irregular pellets)
o (160+180 °C)
+(180 °C)(Irregular pellets)
o (170 °C)
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:6910_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:69 27.10.2010 16:12:00 Uhr27.10.2010 16:12:00 Uhr
Solvent
Polymer Solution Film Casting
Plasticizer
70
4.2.3 Miscibility of Polymer-Plasticizer Combinations
The miscibility of the polymers used in combination with the plasticizers (polymer-plasticizer combinations of 9:1, w / w %) was determined by visual inspection of the mixtures and by determination of the Tgs and Tms by DSC analysis. A homogeneously clear sample is expected to represent completely miscible combinations. In these ex-periments, the mixtures were produced using two different experimental methods.
Polymer: Plasticizer:Kollidon® VA 64 Lutrol® F 68Soluplus® Cremophor® RH 40Kollidon® 12 PF PEG 1500Kollidon® 17 PFKollidon® 30Kollidon® 90 FKollidon® SRKollicoat® MAE 100PKollicoat® IRKollicoat® ProtectLutrol® F 127
Experimental method:1. Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 2.5 to 5 kg / h Extrusion temperature: 60 – 200 °C Screw speed: 100 – 150 rpm
2. Polymer-plasticizer fi lms (fi lm casting): A polymer and a plasticizer were dissol-ved in an appropriate solvent. The solution was cast by Coatmaster (Erichsen Testing Equipment, Germany); the knife had different die gaps (150 – 500 µm) and the solvent was evaporated until a uniform fi lm remained.
Figure 4.2.3-1 Chart of sample production using the fi lm casting method
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7010_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:70 27.10.2010 16:12:00 Uhr27.10.2010 16:12:00 Uhr
71
Table 4.2.3-1 Appearance of polymer-plasticizer com-binations tested by fi lm casting experi-ments / hot-melt extrusion and evaluated by visual inspection
3. Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 (TA Instruments, USA). DSC scans were recorded at a heating rate of 20 K / min during the second heating run.
Clear sample Almost clear sample Opaque sample
- Not extrudable* Not relevant because of
low melting point
Polymer
Lutrol® F 68 Cremophor® RH 40 PEG 1500
Film Extru-date
Film Extru-date
Film Extru-date
Kollidon® VA 64 9:1 9:1 9:1 9:1 9:1 9:1
Soluplus® 9:1 9:1 9:1 9:1 9:1 9:1
Kollidon® 12 PF 9:1 9:1 9:1 9:1 9:1 9:1
Kollidon® 17 PF 9:1 9:1 9:1 9:1 9:1 9:1
Kollidon® 30 9:1 - 9:1 - 9:1 -
Kollidon® 90 F 9:1 - 9:1 - 9:1 -
Kollidon® SR 9:1 9:1 9:1 9:1 9:1 9:1
Kollicoat® MAE 100P 9:1 - 9:1 - 9:1 -
Kollicoat® IR 9:1 9:1 9:1 9:1 9:1 9:1
Kollicoat® Protect 9:1 9:1 9:1 9:1 9:1 9:1
Lutrol® F127 9:1 * 9:1 * 9:1 *
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7110_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:71 27.10.2010 16:12:00 Uhr27.10.2010 16:12:00 Uhr
Heat
Flo
w [W
/g]
8
6
4
2
0
-2-100 -50 0 50 100 150 200
Temperature [°C]
Kollidon VA 64Lutrol F 68Kollidon VA 64 / Lutrol F 68
72
The extrudates of Kollidon® VA 64 in combination with Lutrol® F 68 and Cremophor® RH 40 were opaque, while the extrudate obtained using PEG 1500 was transparent. Based on the DSC results (Figures 4.2.3-2 to 4.2.3-4) and visual inspection, it can be concluded that PEG 1500, in contrast to the others, form a single-phase mixture when melt-extruded with Kollidon® VA 64. This is because, in DSC, no melting point for PEG 1500 was found but rather a shift in the Tg of Kollidon® VA 64. In the case of Lutrol® F 68 and Cremophor® RH 40, melting points could still be detected, showing that these components could not be incorporated homogeneously and complete-ly. Visual inspection of fi lms can be employed as a good indicator for miscibility of components.
Figure 4.2.3-2 DSC plots of Kollidon® VA 64, pure Lutrol® F 68 and the Kollidon® VA 64 / Lutrol® F 68 combination (extrudate, 9:1, w / w %)
Extrudate:Kollidon VA 64 / Lutrol F 68
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7210_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:72 27.10.2010 16:12:01 Uhr27.10.2010 16:12:01 Uhr
Heat
Flo
w [W
/g]
3
2
1
0
-1-100 -50 0 50 100 150 200
Temperature [°C]
Kollidon VA 64Cremophor RH 40Kollidon VA 64 / Cremophor RH 40
Heat
Flo
w [W
/g]
10
8
6
4
2
0
-2-100 -50 0 50 100 150 200
Temperature [°C]
Kollidon VA 64PEG 1500Kollidon VA 64 / PEG 1500
73
Figure 4.2.3-3 DSC plots of Kollidon® VA 64, pure Cremophor® RH 40 and the Kollidon® VA 64 / Cremophor® RH 40 combination (extrudate, 9:1, w / w %)
Figure 4.2.3-4 DSC plots of Kollidon® VA 64, pure PEG 1500 and the Kollidon® VA 64 / PEG 1500 combination (extrudate, 9:1, w / w %)
Extrudate:Kollidon VA 64 / Cremophor RH 40
Extrudate:Kollidon VA 64 / PEG 1500
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7310_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:73 27.10.2010 16:12:01 Uhr27.10.2010 16:12:01 Uhr
74
Table 4.3.1-1 Tested polymer combinations by hot-melt extrusion
4.3 Extrusion of Polymer Mixtures
Kollidon® VA 64 and Soluplus® were selected as two different matrix polymers which were then combined with Kollidon® SR, Kollicoat® IR, Kollidon® 30 and Kollidon® 90 Fto produce different blends.
4.3.1 Extrusion Temperature Range of Polymer Mixtures
The polymer ratios were varied from 100:0 to 0:100 (w / w %) in order to investigate the effect of polymer composition on the minimum processing temperature by extrusion.
Polymer Kollidon® SR Kollicoat® IR Kollidon® 30 Kollidon® 90 F
Kollidon® VA 64 70:30 70:30 70:30 70:30
50:50 50:50 50:50 -
30:70 30:70 30:70 -
Soluplus® 70:30 70:30 70:30 70:30
50:50 50:50 50:50 -
30:70 30:70 30:70 -
Experimental method:Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 4 to 5 kg / h Extrusion temperature: 120 – 200 °C Screw speed: 100 – 150 rpm
In the case of Kollidon® SR, almost no effect of Kollidon® VA 64 on the processing temperature was observed. For all compositions with Kollicoat® IR, it was possible to process the blends at 150 °C. It proved impossible to extrude pure polymers Kollidon® 30 and Kollidon® 90 F due to their high Tg and melt viscosities. In the presence of Kollidon® VA 64, Kollidon® 30 could be melt processed successfully. Moreover, relatively low processing temperatures were required with an increasing amount of Kollidon® VA 64. For Kollidon® 90 F, processing of the mixture was possible only with 70 % (w / w) of Kollidon® VA 64. However, the appearance of the extrudates of this blend was inhomogeneous.
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7410_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:74 27.10.2010 16:12:02 Uhr27.10.2010 16:12:02 Uhr
75
Figure 4.3.1-1 Minimum processing temperature of polymer blends Kollidon® VA 64 and Soluplus® with Kollidon® SR
The blends of Soluplus® with Kollidon® SR could be processed at 135 °C. For all compositions with Kollicoat® IR, the processing temperature could be reduced with increasing amounts of Soluplus®. Also, in the presence of Soluplus®, Kollidon® 30 could be melt-extruded successfully at relatively low processing temperatures by in-creasing the Soluplus® concentration.
The combination of Soluplus® with Kollidon® 90 F behaved similarly to the combina-tion of Kollidon® VA 64 with Kollidon® 90 F but at slightly lower processing tempera-tures. The blends were also inhomogeneous because of the high molecular weight of Kollidon® 90 F.
T pr
oces
sing
[°C]
Kollidon VA 64 Soluplus
240
220
200
180
160
140
120
100
80
60
40
20
0
150135 135 135 135 135
150150150
120
Pure polymerPolymer : Kollidon SR, 70:30Polymer : Kollidon SR, 50:50Polymer : Kollidon SR, 30:70Kollidon SR
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7510_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:75 27.10.2010 16:12:02 Uhr27.10.2010 16:12:02 Uhr
T pr
oces
sing
[°C]
Kollidon VA 64 Soluplus
240
220
200
180
160
140
120
100
80
60
40
20
0
150160
145 150160 160
150150150
120
Pure polymerPolymer : Kollicoat IR, 70:30Polymer : Kollicoat IR, 50:50Polymer : Kollicoat IR, 30:70Kollicoat IR
T pr
oces
sing
[°C]
Kollidon VA 64 Soluplus
240
220
200
180
160
140
120
100
80
60
40
20
0
190175
160150
200190
175
120
Pure polymerPolymer : Kollidon 30, 70:30Polymer : Kollidon 30, 50:50Polymer : Kollidon 30, 30:70
76
Figure 4.3.1-2 Minimum processing temperature of polymer blends Kollidon® VA 64 and Soluplus® with Kollicoat® IR
Figure 4.3.1-3 Minimum processing temperature of polymer blends Kollidon® VA 64 and Soluplus® with Kollidon® 30
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7610_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:76 27.10.2010 16:12:03 Uhr27.10.2010 16:12:03 Uhr
T pr
oces
sing
[°C]
Kollidon VA 64 Soluplus
240
220
200
180
160
140
120
100
80
60
40
20
0
190
150
185
120
Pure polymerPolymer : Kollidon 90 F, 70:30
77
Figure 4.3.1-4 Minimum processing temperature of polymer blends Kollidon® VA 64 and Soluplus® with Kollidon® 90 F
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7710_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:77 27.10.2010 16:12:03 Uhr27.10.2010 16:12:03 Uhr
78
4.3.2 Appearance and Pelletizing Characteristics of Ext-rudates of Polymer Mixtures
The appearance of the extrudates and pelletizing behavior of the polymer mixtures are important characteristics, particularly for downstream processing.
The two different matrix polymers Kollidon® VA 64 and Soluplus® in combination with Kollidon® SR, Kollicoat® IR, Kollidon® 30 and Kollidon® 90 F showed good pelletizing behavior. The appearance of the extrudates of these blends was opaque and dis-played the inhomogeneous nature of the systems.
Table 4.3.2-1 Overview of appearance (A) and pelletizing (P) behavior of polymer mixtures
Kollidon® SR Kollicoat® IR
P A P A
Kollidon® VA 64 + 100:0 + 100:0
+ 70:30 + 70:30
+ 50:50 + 50:50
+ 30:70 + 30:70
+ 0:100 + 0:100
Soluplus® + 100:0 + 100:0
+ 70:30 + 70:30
+ 50:50 + 50:50
+ 30:70 + 30:70
+ 0:100 + 0:100
Kollidon® 30 Kollidon® 90 F
P A P A
Kollidon® VA 64 + 100:0 + 100:0
+ 70:30 + 70:30
+ 50:50 Not processable! 50.50
o 30:70 Not processable! 30:70
Not processable! 0:100 Not processable! 0:100
Soluplus® + 100:0 + 100:0
+ 70:30 + 70:30
+ 50:50 Not processable! 50.50
o 30:70 Not processable! 30:70
Not processable! 0:100 Not processable! 0:100
Clear sample Almost clear sample Opaque sample
+ Good pelletizing behavioro Poor pelletizing behavior
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7810_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:78 27.10.2010 16:12:03 Uhr27.10.2010 16:12:03 Uhr
Cl C O O CH(CH3)2C
CH3
CH3
CO
O
N
CO NH2
Cl
Cl
NN
NO O
O
OH
N N NN
N
C2H5CH
CH3
79
Figure 4.4-1 Model drugs
4.4 Solubilization Capacity of Active Ingredients in Polymers for Hot-Melt Extrusion
The solubilization capacity of active pharmaceutical ingredients in solid solutions of the following polymers was investigated.
Kollidon® VA 64 Kollidon® 30 with 10 % PEG 1500 (w / w %)Soluplus® Kollidon® 90 F with 20 % PEG 1500 (w / w %)Kollidon® 12 PF Kollicoat® MAE 100 P with 10 % PEG 1500 (w / w %)Kollidon® 17 PF Kollicoat® IR with 10 % PEG 1500 (w / w %)Kollidon® SR Kollicoat® Protect with 10 % PEG 1500 (w / w %)Lutrol® F 127
The APIs fenofi brate, carbamazepine and itraconazole were used as model drugs be-cause of their low solubility. Some polymers had to be combined with 10 – 20 % (w / w) PEG 1500 in order to enable extrusion processing at appropriate temperatures.
Fenofi brate (antihypertensive)~0.0001 g / 100 mLin phosphate buffer pH 7.0
Itraconazole (fungicide)~0.0001 g / 100 mLin phosphate buffer pH 7.0
Carbamazepine (antiepileptic)~0.013 g / 100 mLin phosphate buffer pH 7.0
The solubilization capacity of the APIs in the solid solutions of the polymers was deter-mined using the two different methods of fi lm casting and hot-melt extrusion.
4
10_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:7910_P_0380_BASF_Buch_HotMelt_40_79.indd Abs1:79 27.10.2010 16:12:04 Uhr27.10.2010 16:12:04 Uhr
Solvent
Dried polymer film
Active
Polymer orPolymer/plasticizer combinations
80
Figure 4.4.1-1 Film casting procedure
4.4.1 Film Casting
Solubilization capacity was determined by fi lm casting experiments using fenofi brate, carbamazepine and itraconazole as model drugs in combination with the polymers or polymer-plasticizer combinations described below.
Experimental method:Film casting: An appropriate solvent that dissolves the API, the polymer and the plasticizer should be selected. When the substances are dissolved after stirring, the solution can be cast on a glass plate, resulting in a thin fi lm. A scraper that produces a fi lm of 120 µm thickness is recommended as casting device. The thin fi lm (thickness of the dry fi lm <120 µm) enables fast drying and avoids the recrystallization of the poorly soluble drug that can occur when high drug concentrations are used over a longer period, as happens in case of thick fi lms. Drying should be performed for 30 minutes under ambient conditions (fl ue) and then in a vacuum drying cabinet (50 °C, 10 mbar for 30 minutes) to ensure fast and complete drying of the fi lm. To analy-ze the extent of solubilization capacity of the polymer or of the polymer-plasticizer combination for a specifi c drug, increasing amounts of API should be applied for the fi lm casting method (25, 33 and 50 %). The higher the clearly dissolved drug con-centration, the higher the solubilization capacity. A solid solution results in clear and smooth fi lms. Drug crystals can easily be recognized as can amorphous precipitation (opaque fi lms). Visual inspection of the fi lms was performed 7 days after open storage at 23 °C / 54 % r. h.
Preparation of fi lms with 25 %, 33 % and 50 % drug content
Observation of fi lm stability drug must not re-crystallize
Blanksample
Crystallinesample
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8010_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:80 27.10.2010 16:14:27 Uhr27.10.2010 16:14:27 Uhr
81
Table 4.4.1-1 Solubilization capacity of fenofi brate, carb-amazepine and itraconazole in polymers or polymer-plasticizer combinations
Soluplus® showed the highest solubilization capacity followed by Kollidon® VA 64 and Kollidon® SR. Kollidons of the lower molecular weight such as Kollidon® 12 PF and Kollidon® 17 PF dissolved only smaller amounts. For the systems comprising Kollicoat® MAE 100P, Kollicoat® IR and Kollicoat® Protect in combination with itraco-nazole, no appropriate solvent could be found that dissolved all components.
* With 10 % PEG 1500 ** With 20 % PEG 1500
PolymerDrug content [% dissolved in polymer]
Fenofi brate Carbamazepine Itraconazole
Kollidon VA 64 25 – 33 33 – 50 >50
Soluplus 33 – 50 33 – 50 >50
Kollidon 12 PF 25 – 33 25 – 33 33 – 50
Kollidon 17 PF <25 25 – 33 33 – 50
Kollidon 30 * <25 <25 >50
Kollidon 90 F ** <25 <25 >50
Kollidon SR 25 – 33 33 – 50 >50
Kollicoat MAE 100P * <25 >50 n. d.
Kollicoat IR * <25 <25 n. d.
Kollicoat Protect * <25 <25 n. d.
Lutrol F 127 <25 <25 <25
High solubility of API Good solubility of API Low solubility of API
n. d. Not detected
4
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8110_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:81 27.10.2010 16:14:33 Uhr27.10.2010 16:14:33 Uhr
82
4.4.2 Extrusion
Besides the fi lm experiments, solubilization capacity was also determined using hot-melt extrusion of carbamazepine and itraconazole as model drugs in combination with the following polymers and polymer-plasticizer combinations:
Kollidon® VA 64 Kollidon® 30 with 10 % PEG 1500 (w / w %)Soluplus® Kollidon® 90 F with 20 % PEG 1500 (w / w %)Kollidon® 12 PF Kollicoat® MAE 100P with 10 % PEG 1500 (w / w %)Kollidon® 17 PF Kollicoat® IR with 10 % PEG 1500 (w / w %)Kollidon® SR Kollicoat® Protect with 10 % PEG 1500 (w / w %)Lutrol® F 127
Drug content in the extrudates was increased from 10 % to 50 % (w / w) in 5 % steps. All extrudates were investigated by X-ray Diffraction (XRD) or DSC in order to determi-ne the physical state of the incorporated drug. Since stability of solid dispersions can be a critical point, the extrudates were stored in open glass bottles at 25 °C / 60 % r.h. for 3 months and tested for physico-chemical changes. In addition dissolution studies were also performed.
Figure 4.4.2-1 Appearance of extrudates with increasing drug concentration
Increasing drug concentration (w / w %)
25 % 30 % 35 % 40 % 45 % 50 %
Experimental method:1. Extrusion: Melt extrusion was performed using a twin-screw extruder PolyLab OS (ThermoFisher, Germany) with a screw diameter of 16 mm and a length to diameter ratio of 40D. Several extrusion parameters were varied such as the loading of the extruder (from 0.3 to 0.8 kg / h), extrusion temperature (90 – 180 °C) and the speed of the extruder screws (from 50 to 250 rpm). The active ingredient was fed to the
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8210_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:82 27.10.2010 16:14:33 Uhr27.10.2010 16:14:33 Uhr
Lin
(Cou
nts)
4614
02 10 20 30
2-Theta-Scale
Amorphous systemCrystalline systemItraconazole
83
Figure 4.4.2-2 ThermoFisher Extruder PolyLab OS and the extruder equipment used in the trials
Extruder Equipment:: 16 mm screw diameter Different screw elements Variable length of 25 or 40D Gravimetric dosing system Volumetric dosing system Gear pump Belt conveyor Pelletizing device
extruder via a separate feeder, since this allows a simple and quick change of the active concentration in the extrudate. After extrusion, the samples were cooled down on a conveyor belt and subsequently pelletized.
Figure 4.4.2-3 XRD examples of extrudates of Kollidon® VA 64 with itraconazole and the pure API itraconazole
2. X-ray Diffraction (XRD): XRD studies were performed by using a diffractometer D 8 Advance (Bruker / AXS, Germany).
3. Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 (TA Instruments, USA). DSC scans were recorded at a heating rate of 20 K / min during the fi rst heating run.
4
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8310_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:83 27.10.2010 16:14:35 Uhr27.10.2010 16:14:35 Uhr
84
Table 4.4.2-1 Solubilization capacity of the APIs carbamazepine and itraconazole in polymers or polymer-plasticizer combinations. XRD / DSC analysis reveals the highest concentration of dissolved / amorphous active in the polymer (absence of crystal peaks)
Polymer
Drug content [% dissolved in polymer]
Carbamazepine [mp: 190 – 193 °C]
Itraconazole [mp: 166.2 °C]
Kollidon® VA 64
Process temperature 150 – 160°C 155 °C
Extrudates (initial value) 35 % 40 %
Extrudates (1 month) 35 % 40 %
Extrudates (3 months) 30 % 40 %
Soluplus®
Process temperature 150 – 160 °C 160 °C
Extrudates (initial value) 30 % >50 %
Extrudates (1 month) 30 % >50 %
Extrudates (3 months) 30 % >50 %
Kollidon® 12 PF
Process temperature 120 – 130 °C 130 °C
Extrudates (initial value) <15 % <25 %
Extrudates (1 month) <15 % <25 %
Extrudates (3 months) <15 % <25 %
Kollidon® 17 PF
Process temperature 160 – 170 °C 150 – 160 °C
Extrudates (initial value) 35 % 40 %
Extrudates (1 month) 30 % 40 %
Extrudates (3 months) 15 % (DSC) 40 %
Kollidon® 30 + 10 % PEG 1500
Process temperature 140 – 170 °C 160 – 170 °C
Extrudates (initial value) 35 % > 50 %
Extrudates (1 month) 35 % > 50 %
Extrudates (3 months) 10 % > 50 %
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8410_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:84 27.10.2010 16:14:36 Uhr27.10.2010 16:14:36 Uhr
85
Polymer
Drug content [% dissolved in polymer]
Carbamazepine [mp: 190 – 193 °C]
Itraconazole [mp: 166.2 °C]
Kollidon® 90 F + 20 % PEG 1500
Process temperature 180 °C 160 °C
Extrudates (initial value) >50 % > 50%
Extrudates (1 month) 10 % > 50%
Extrudates (3 months) 10 % > 50%
Kollidon® SR
Process temperature 150 °C 150 °C
Extrudates (initial value) 25 % 45 %
Extrudates (1 month) 25 % 45 %
Extrudates (3 months) 20 % 45 %
Kollicoat® MAE 100P + 10 % PEG 1500
Process temperature Not processable!
Kollicoat® IR + 10 % PEG 1500
Process temperature 140 °C 140 °C
Extrudates (initial value) <20 % 25 %
Extrudates (1 month) <20 % <15 %
Extrudates (3 months) <20 % <15 %
Kollicoat® Protect + 10 % PEG 1500
Process temperature 140 °C 145-150 °C
Extrudates (initial value) <10 % <20 %
Extrudates (1 month) <10 % <20 %
Extrudates (3 months) <10 % <20 %
Lutrol® F 127
Process temperature 140 °C 140 °C
Extrudates (initial value) 30 % <15 %
Extrudates (1 month) <10 % <15 %
Extrudates (3 months) <10 % <15 %
4
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8510_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:85 27.10.2010 16:14:37 Uhr27.10.2010 16:14:37 Uhr
Solu
biliz
atio
n ca
paci
ty A
PI [%
]
KollidonVA 64
Kollidon12 PF
Kollidon17 PF
Kollidon30*
Kollidon90 F**
KollidonSR
KollicoatIR*
KollicoatProtect*
Lutrol F127
Soluplus
60
50
40
30
20
10
0
XRD BeginningXRD 1 Month (25 °C/60% RH)XRD 3 Months (25 °C/60% RH)
* Polymer + 10% PEG 1500** Polymer + 20% PEG 1500 Solubilization capacity API below the tested concentration Solubilization capacity API above the tested concentration
86
Carbamazepine extrudatesPrincipally, there are two types of polymer – those that can solubilize higher concen-trations and those of rather poor performance in this respect. Differences were also found when storing the solid solutions for a longer period of time. Kollidon® VA 64 and Soluplus® could solubilize >_ 30 % (w / w) carbamazepine and kept it in solution for more than 3 months. The other polymers such as Kollidon® 12 PF, Kollidon® SR, Kollicoat® IR and Kollicoat® Protect were less effective for the solubilization of carbamazepine (< 30 % (w / w)). Some polymers resulted in quite high concentrations at the beginning (Kollidon® 17 PF, Kollidon® 30, Kollidon® 90 F and Lutrol® F 127); however, the drug crystallized upon storage and the concentration of dissolved drug decreased signifi cantly.
Figure 4.4.2-4 Stability of carbamazepine extrudates stored in open glass bottles at 25 °C / 60 % r.h. over a period of 3 months
Itraconazole extrudatesMost of the polymers dissolved itraconazole better than carbamazepine and con-centrations of >_ 40 % (w / w) could mostly be achieved. Best performance > 50 % was obtained for Soluplus®, Kollidon® 30 + 10 % PEG 1500 and Kollidon® 90 F + 20 % PEG 1500 followed by Kollidon® SR with 45 %, Kollidon® VA 64 with 40 % and Kol-lidon® 17 PF with 40 %. Kollicoat® IR, Kollicoat® Protect and Lutrol® F 127 are too hydrophilic by far to dissolve lipophilic actives. Changes upon storage occurred only with Kollicoat® IR, whereas all the others remained stable.
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8610_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:86 27.10.2010 16:14:37 Uhr27.10.2010 16:14:37 Uhr
Solu
biliz
atio
n ca
paci
ty A
PI [%
]
KollidonVA 64
Kollidon12 PF
Kollidon17 PF
Kollidon30*
Kollidon90 F**
KollidonSR
KollicoatIR*
KollicoatProtect*
Lutrol F127
Soluplus
60
50
40
30
20
10
0
XRD BeginningXRD 1 Month (25 °C/60% RH)XRD 3 Months (25 °C/60% RH)
* Polymer + 10% PEG 1500** Polymer + 20% PEG 1500 Solubilization capacity API below the tested concentration Solubilization capacity API above the tested concentration
87
Figure 4.4.2-5 Stability of itraconazole extrudates stored in open glass bottles at 25 °C / 60 % r.h. over a period of 3 months
4.4.3 Results and Comparison
The solubilization capacity of the APIs carbamazepine and itraconazole in solid solu-tions of the polymers was determined using the two different methods of fi lm casting and hot-melt extrusion. Extruders require considerable quantities of drugs, which are not often available at the early development stage when pilot studies are undertaken. In contrast to extrusion studies, fi lm tests can be performed with small amounts of drugs. In case there would be a correlation between extrusion and fi lm tests, the latter can serve as an indicator for solid solutions, provide an approximate drug / excipient ratio and minimize the number of extrusion experiments. For this comparison, solubi-lization capacities from fi lm casting (7 days / 23 °C / 54 % r. h.) and extrusion (1 month at 25 °C / 60 % r. h.) were used. Differences in results between the two methods might well be because, in hot-melt extrusion, no solvent is used and the drug is incorpora-ted by temperature and shear only, whereas in fi lm casting the solid solution is formed by evaporation of the solvent.
4
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8710_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:87 27.10.2010 16:14:37 Uhr27.10.2010 16:14:37 Uhr
Solu
biliz
atio
n ca
paci
ty A
PI [%
]
KollidonVA 64
Kollidon12 PF
Kollidon17 PF
Kollidon30*
Kollidon90 F**
KollidonSR
KollicoatIR*
KollicoatProtect*
Lutrol F127
Soluplus
60
50
40
30
20
10
0
Film casting Extrusion * Polymer + 10% PEG 1500** Polymer + 20% PEG 1500 Solubilization capacity API below the tested concentration
88
Solubilization capacities of carbamazepineA good correlation of fi lm casting and extrusion results was achieved for carbamaze-pine extrudates with Kollidon® VA 64, Kollidon® 17 PF, Kollidon® 90 F + 20 % PEG 1500, Kollicoat® IR + 10 % PEG 1500, Kollicoat® Protect + 10 % PEG 1500 and Lutrol® F 127. The other systems (except Kollidon® 30 + 10 % PEG 1500) showed higher solubilization capacities in fi lm casting experiments.
Figure 4.4.3-1 Comparison of the solubilization capacity of carbamazepine determined by fi lm casting (visual inspection 7 days after storage at 23 °C / 54 % r. h.) and extrusion (XRD 1 month after storage in open glass bottles at 25 °C / 60 % r. h.)
Solubilization capacities of itraconazoleThe combinations of itraconazole with Soluplus®, Kollidon® 17 PF, Kollidon® 30 + 10 % PEG 1500, Kollidon® 90 F + 20 % PEG 1500 and Lutrol® F 127 revealed good correlation between extrusion and fi lm casting. Higher solubilization capacities in fi lm casting were observed with the other combinations.
In principle, solubilization capacities determined by extrusion and fi lm casting correla-te well and therefore the fi lm casting method is a suitable tool for predicting the ma-ximum concentration of dissolved drug in the polymer. The solubilization capacities determined by fi lm casting have a tendency to produce higher values compared to the results obtained by extrusion.
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8810_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:88 27.10.2010 16:14:38 Uhr27.10.2010 16:14:38 Uhr
Solu
biliz
atio
n ca
paci
ty A
PI [%
]
KollidonVA 64
Kollidon12 PF
Kollidon17 PF
Kollidon30*
Kollidon90 F**
KollidonSR
Lutrol F127
Soluplus
70
60
50
40
30
20
10
0
* Polymer + 10% PEG 1500** Polymer + 20% PEG 1500 Solubilization capacity API below the tested concentration Solubilization capacity API above the tested concentration
Film casting Extrusion
89
Figure 4.4.3-2 Comparison of the solubilization capacity of itraconazole determined by fi lm casting (visual inspection 7 days after storage at 23 °C / 54 % r. h.) and extrusion (XRD 1 month after storage in open glass bottles at 25 °C / 60 % r. h.)
4
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:8910_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:89 27.10.2010 16:14:38 Uhr27.10.2010 16:14:38 Uhr
90
5 In-Vitro / In-Vivo Characteristics of HME Formulations
5.1 In-Vitro Release Characteristics of HME Formulations
Drug dissolution is an important parameter for the characterization of a solid disper-sion since it reveals whether the drug dissolves completely or not and whether the polymer prevents crystallization and keeps the drug in an oversaturated dissolved state. Thus, all experiments were carried out without the addition of any further solu-bilizer in the dissolution medium (non-sink conditions).
Three different types of behavior of drugs formulated with water-soluble polymers can occur:1. The drug dissolves and no recrystallization takes place.2. The drug dissolves and later recrystallization occurs, leading to a decrease of the
dissolution curve.3. Crystallization occurs quickly and almost simultaneously with the matrix dissolving,
leading to a very low and incomplete dissolution curve.
It is quite obvious that the targeted profi le is behavior No. 1 – complete release without recrystallization.
Experimental method:Drug release: Drug release was tested according to USP, with apparatus 2, 50 rpm 700 mL HCl (0.08 N) under non-sink conditions. Release was determined using cut extrudates of comparable length (3 mm in length and diameter, except Lutrol® F 127, as this could not be cut directly into pellets). The amount of API used was 100 mg. During dissolution, samples were automatically taken through a fi lter of size 45 µm and immediately measured by the 8453 UV-Visible spectrophotometer (Agilent, USA).
All polymers or polymer-plasticizer combinations with itraconazole showed an en-hanced dissolution rate of the drug (except Kollidon® SR) compared to the crystalline itraconazole.
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9010_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:90 27.10.2010 16:14:38 Uhr27.10.2010 16:14:38 Uhr
Drug
rele
ase
[%]
100
90
80
70
60
50
40
30
20
10
00 30 60 90
t [min]120
30% Itraconazole in Kollidon VA 6428% Itraconazole in Soluplus20% Itraconazole in Kollidon SR26% Itraconazole in Kollicoat IR + 10% PEG 150028% Itraconazole in Kollicoat Protect + 10% PEG 150024% Itraconazole in Lutrol F 127Itraconazole
91
Figure 5.1-1 Drug release of pelletized itraconazole extrudates, 100 mg API
Soluplus® outperformed all other polymers by far and resulted in almost complete dissolution. From these results it is obvious that Soluplus® is capable of solubilizing itraconazole effectively, not only in a solid state but also in an aqueous environment; it is also capable of preventing crystallization. In this case a high level of supersaturation (approx. 20-fold) is achieved and maintained. Satisfactory results were found with Kollicoat® IR and Kollidon® VA 64.
Within the range of PVP homopolymers, Kollidon® 90 F produced signifi cant dissolu-tion of itraconazole, whereas, with decreasing molecular weight of the PVP homopo-lymer, dissolution decreased.
5
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9110_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:91 27.10.2010 16:14:38 Uhr27.10.2010 16:14:38 Uhr
Drug
rele
ase
[%]
100
90
80
70
60
50
40
30
20
10
00 30 60 90
t [min]120
22% Itraconazole in Kollidon 12 PF24% Itraconazole in Kollidon 17 PF28% Itraconazole in Kollidon 30 + 10% PEG 150034% Itraconazole in Kollidon 90 F + 20% PEG 1500Itraconazole
92
Figure 5.1-2 Drug release of pelletized itraconazole extrudates, 100 mg API
5.2 In-Vivo Behavior of HME Formulations
When developing formulations for poorly soluble drugs, the general target is to incre-ase bioavailability. This cannot be tested in in-vitro experiments but only in in-vivo stu-dies, either in animals or in humans. Of course, the in-vitro dissolution characteristics give some indication of the effi cacy in humans but often there is no exact in-vitro – in-vivo correlation; the dissolution behavior of a drug formulation in a glass vessel and in the intestine under the infl uence of ingested food and intestinal motility might well be different. However, almost complete in-vitro dissolution combined with a high degree of supersaturation maintained over a longer period of time are essential prere-quisites for a signifi cant increase in bioavailability. This does not necessarily mean, of course, that the quickest dissolution always leads to the best bioavailability.
In order to show the potential of HME formulations for increasing bioavailability, a study on itraconazole as a model drug was performed.
Experimental method:The following drug formulations were produced and used:1. Solid solution: Itraconzole was extruded with Soluplus® to result in a 15 % solid solution. The extrudates were milled, blended with 5 % of disintegrant and fi lled into gelatine capsules.
2. Physical mixture: Itraconazole, Soluplus® and disintegrant were blended in the same proportions as in the solid solution and fi lled into gelatine capsules.
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9210_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:92 27.10.2010 16:14:39 Uhr27.10.2010 16:14:39 Uhr
Bloo
d co
ncen
tratio
n [n
g/m
L]
450
400
350
300
250
200
150
100
50
00 5 10 20
Time [h]15 25
Solid solution itraconazoleCrystalline itraconazolePhysical mixture itraconazole
93
Figure 5.2-1 Blood concentration of itraconazole applied to beagle dogs in different formulations
3. Crystalline drug: Itraconazole was blended with disintegrant and fi lled into gelatine capsules.
Animal study:The formulations were applied to 5 beagle dogs (in fasting state) in a dose of 10 mg / kg body weight. Plasma samples were taken at eight predetermined time points and analyzed for itraconazole concentration.
The plasma curves reveal that itraconazole is a drug which is poorly absorbed wit-hout special formulations. The crystalline drug as well as the physical mixture with Soluplus® did not result in signifi cant plasma levels. In contrast, the solid solution of itraconazole in Soluplus® signifi cantly enhanced the absorption. This study de-monstrates that the physico-chemical properties and the in-vitro characteristics of Soluplus® are capable of achieving the desired in-vivo performance.
5
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9310_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:93 27.10.2010 16:14:39 Uhr27.10.2010 16:14:39 Uhr
94
6 Manufacture of Final Dosage Forms
The extrusion process leads to a strand leaving the die in a more or less molten or softened state; this then solidifi es upon cooling and is commonly cut into pieces in the mm range by a pelletizer. The still soft strand or ribbon can also be directly shaped into forms similar to tablets by a calender, which consists of two co-rotating rolls with cavities. The principle of manufacturing has some similarities to the soft gel capsule manufacturing process.
The cut extrudates can be fi lled into hard gelatine capsules, but usually the extrudates are milled in order to speed up the release rate. Such milled solid solutions can be blended with other excipients and either fi lled into capsules or compressed into tab-lets. In each case it is recommended to use water-insoluble excipients acting as so called spacers between the solid solution particles in order to avoid lumping effects when the dosage form comes into contact with water. Such lumping can negatively affect the dissolution rate due to reduced surface area and longer diffusion pathways. Water-insoluble excipients separate the particles of the solid solution and prevent lumping. Best results were found with crospovidone (Kollidon® CL, CL-F, CL-SF) and microcrystalline cellulose, but dicalcium phosphate and other inorganic excipients can also be employed.
Typically, tablets containing solid solution particles require higher disintegrant con-centrations (5 to 20 %) than common ones (3 to 5 %). Here, crospovidone, due to its limited swelling behavior, outperforms all other superdisintegrants (croscarmellose sodium, sodium starch glycolate), which are of unlimited swelling and form gels upon contact with water.
Examples of dosage forms1. Capsule formulation:Solid solution 70 % (w / w)Kollidon® CL 15 % (w / w)Microcrystalline cellulose 15 % (w / w)
2. Tablet formulation:Solid solution 60 % (w / w)Microcrystalline cellulose (Avicel® PH 102) 29 % (w / w)Kollidon® CL 10 % (w / w)Magnesium stearate 0.5 % (w / w)Aerosil® 200 0.5 % (w / w)
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9410_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:94 27.10.2010 16:14:39 Uhr27.10.2010 16:14:39 Uhr
95
7 Flow Chart: From Screening to a Final Pharmaceutical Formulation
The following fl ow chart shows the development process from screening to a fi nal pharmaceutical formulation using hot-melt extrusion.
Figure 7-1 From screening to a fi nal pharmaceutical formulation
Polymer API AdditiveSelection by:- Chemical structure- Solubility- Glass transition temperature (Tg)- Melt Viscosity- Lipophilicity- Dissolution profile- Stability
Relevant characteristics:- Solubility- Melting point (Tm)- Lipophilicity- Stability
Selection by:- Physical state- Plasticizing effect- Lubricating effect- Stability
Decisive parameters:- Solubilization capacity- Appearance- Miscibility
Decisive parameters:- Processability- Torque- Temperature- Pelletizing
Decisive parameters:- Solubilization capacity- Appearance- Dissolution- Physical state
Decisive parameters:- Processability- Stickiness- Particle size- Excipients for tabletting
Decisive parameters:- Appearance- Dissolution- Stability- Bioavailability- Physical state
Polymer/API /Additive
Pre-study:Film casting trials
Hot-melt extrusion
Extrudate
Milling/tableting/capsule filling
Final oral dosage form
Stability tests
Stability tests
6
7
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9510_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:95 27.10.2010 16:14:39 Uhr27.10.2010 16:14:39 Uhr
96
8 Practical Recommendations for Extrusion
Hot-melt extrusion (HME) is still a process which is not yet well established in the pharmaceutical industry. It is a relatively new technology for pharmaceuticals and there is therefore a lack of practical experience; thus formulators have had to start from scratch. In this chapter fi rst recommendations for carrying out extrusion expe-riments are given.
General recommendation for the process1. Impact of ingredient characteristicsWhen starting the development process for pharmaceutical formulations using HME, it is important to select suitable polymers and additives, as described in the fl ow chart illustrated in chapter 7: From Screening to a Final Pharmaceutical Formulation.
Important factors that infl uence the process parameters in HME are:
Polymer characteristics: Glass transition temperature or melting temperature, melt viscosity and thermal stability.
Additive characteristics: Thermal stability, plasticizing effect and lubricating effect. API characteristics: Thermal stability, plasticizing effect and melting point.
2. Correlation between extrusion parametersThe impact of the so-called independent variables such as screw speed, feed rate and temperature on parameters such as torque and residence time should be known for each extruder and basic formulation (as described in chapter 1: Introduction to Hot-Melt Extrusion for Pharmaceuticals). This allows a better comparison and a better understanding of extrusion experiments carried out at different settings. In particular, it is a prerequisite for the scale-up of extrusion processes from small extruders (16 or 18 mm screw diameter) to pilot plant scale (approximately 25 mm screw diameter) and hence to production scale (40 to 70 mm screw diameter).
3. Constant and equilibrated processIn principle, extrusion is a continuous process where materials enter the machine at one side and leave it at the other. All settings should be such that the whole process runs in a constant, equilibrated and smooth manner. This is of particular importance when taking samples from the extruded material for further analysis. Torque, through-put and die pressure are good indicators for such a process and they should not vary much.
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9610_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:96 27.10.2010 16:14:40 Uhr27.10.2010 16:14:40 Uhr
97
Feeder1. Demixing of the blend during feeding Verifi cation of homogeneous mixing of the blend by horizontal and vertical mixing
in the feeder. Separate feeding of ingredients should be used in case of segregation of a mix-
ture. Generally, this allows quick changes of the formulation. If the active is fed by a separate feeder, its concentration in the polymer matrix can be changed simply by adjusting its feed rate while keeping the feed rate of the other ingredients constant.
2. Segregation of blendsTo avoid segregation, powders of almost the same particle size should be used. For instance, Lµtrol® micro grades usually do not segregate because they have a similar particle size (50 µm) to actives in contrast to the Lutrol® F grades, which are in the mm-range. If segregation cannot be avoided, the ingredients should be fed to the extruder by separate feeders.
3. Electrostatic charge on the substances Grounding of the equipment. Appropriate design of the screw tube. Electrostatic charge on the API: Polymer / API premix preparation can avoid this. Anti-static solutions (U-electrode) generate positive and negative ions evenly and
hence remove charges from the substance.
4. Inconstant feedingAn appropriate twin-screw for the feeder should be selected. It should run well within the feeding range of the twin-screw expressed as kg / h. Particle size and other phy-sical characteristics of the formulation determine the screw geometry / design of the feeder.
5. Gravimetric feeding systemsGravimetric feeding systems should be run in a constant and protected environment without vibrations and infi ltration (drafts!).
Feeding section of the twin-screw extruder1. Cooling the feeding sectionThe powder must not melt within the fi rst barrels after the feeding sections to avoid blocking the barrel opening.
2. Screw confi gurationOnly conveying elements should be used in the feeding section and afterwards for a certain distance. A narrow distance between the barrel opening and the fi rst kneading block can lead to backfl ow of powder and inconstant throughput.
8
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9710_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:97 27.10.2010 16:14:40 Uhr27.10.2010 16:14:40 Uhr
98
Melting section of the twin-screw extruder1. Melting of the formulation should be brought about by a balanced combination of thermal and mechanical energy. Factors to be taken into consideration are glass transition temperature or melting temperature and melt viscosity of the ingredients, screw speed, feed rate, screw confi guration, barrel temperature etc. The energy input caused by friction should not dominate the process as high temperature peaks can occur in small areas.
2. Start-up of a twin-screw extruder Start with a moderate screw speed. Adjust the feed rate according to the melt viscosity of the material (high melt
viscosity of the powder means lower feed rate).
Mixing section of the twin-screw extruder1. Adjustment of mixing intensityIn principle, as much as needed, as low as possible. Parameters: Length of the mixing section and the confi guration of the kneading elements (a strong increase in tempe-rature in the kneading sections should be avoided!).
2. Screw confi gurationFor thermal- and shear-sensitive polymers and APIs, a screw confi guration providing low shear should be selected.
Degassing section of the twin-screw extruder1. Removal of residual moisture of the powder in the extrusion process.
2. Application of vacuumThis is for quicker removal of moisture and removal of entrapped air and gas bubbles.
3. Screw confi gurationConveying elements only should be used in the degassing section.
Die1. Bulky surface of the extrudatesReduction of die temperature for increasing die pressure; pressures can also be changed by altering the dimensions of the die.
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9810_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:98 27.10.2010 16:14:40 Uhr27.10.2010 16:14:40 Uhr
99
Pelletizing device1. Poor pelletizing properties of extrudates caused by stickinessImprovement can be achieved by pre-cooling the extrudates with cold air between die and pelletizing device.
2. Poor pelletizing properties of extrudates caused by brittlenessPelletizing of immediately cooled strands to room temperature can be diffi cult if the material becomes brittle upon cooling. In this case, prevent the temperature of the strands from reaching a low value before pelletizing.
Sampling1. All samples should be taken from a constant and equilibrated process.
2. If release rates are to be determined from pelletized extrudates, the geometry of the pellets (diameter, length, surface area) should be very similar.
8
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:9910_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:99 27.10.2010 16:14:40 Uhr27.10.2010 16:14:40 Uhr
100
9 Regulatory Aspects
In this chapter, an overview is given on the regulatory status of the BASF pharma polymers.
Table 9-1 Regulatory status of BASF pharma polymers and plasticizers
USA Europe JapanGRAS Status USA
Maximum Potency * [mg]
Kollidon® VA 64 + + + +** 854
Kollidon® 30 + + + +**** 80
Polyvinyl acetate + + + - 46
Kollicoat® MAE 30 DP + + + - 100
Kollicoat® IR+ + + Expected
Q1 201120.4***
Lutrol® F 127 + + + - 107
Lutrol® F 68 + + + - 66.9
Cremophor® RH 40 + + - - 405
PEG 1500 + + + - 4.2*****
+ Approved in drug formulations* According to FDA Inactive Ingredient Guide** Self-affi rmed GRAS status*** According to registration in various European
countries**** Grandfathered***** Polyethylene glycols with slightly lower or
higher molecular weights are listed with much higher quantities
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10010_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:100 27.10.2010 16:14:40 Uhr27.10.2010 16:14:40 Uhr
101
Typically, in extruded formulations, more polymer is used compared to common ap-plications such as coatings or binders since the polymer serves as a matrix. BASF pharma polymers either benefi t from prolonged use in pharmaceutical applications (e. g. older products such as Kollidon® 30) or they have been tested over the full range of toxicological studies (e. g. newer products such as Soluplus® or Kollicoat® IR). In most cases, the results obtained from toxicological studies justify higher doses than the ones given in Table 9-1 of the FDA Inactive Ingredient Guide.
Toxicological expert reports are available upon request.
9
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10110_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:101 27.10.2010 16:14:41 Uhr27.10.2010 16:14:41 Uhr
102
10 Literature References
1. H. H. Görtz, R. Klimesch, K. Lämmerhirt, S. Lang, A. Sanner, R. Spengler, Verfahren zur Herstellung von festen pharmazeutischen Formen, EP 0240904 B1.
2. J. Breitenbach, B. Wiesner, The use of polymers in pharmaceutical melt extrusi-on, ExAct 20, 8-11 (2008).
3. N. Follonier, E. Doelker, E. T. Cole, Various ways of modulating the release of dialtiazem hydrochloride from hot-melt extruded sustained release pellets using polymeric materials, J. Contr. Release, 36(3), 243-250 (1995).
4. D. Djuric, P. Kleinebudde, Continuous granulation with a twin-screw extruder, Dissertation (2008).
5. N. Follonier, E. Doelker, E. T. Cole, Evaluation of hot-melt extrusion as a new technique for the production of polymer-based pellets for sustained release capsules containing high loadings of freely soluble drugs, Drug Dev. Ind. Pharm., 20(8), 1323-1339 (1994).
6. C. R. Young, J. J. Koleng, J. W. McGinity, Production of spherical pellets by a hot-melt extrusion and spheronization process, Int. J. Pharm. 242, 87-92 (2002).
7. M. M. Crowley, B. Schroeder, A. Fredersdorf, S. Obara, M. Talarico, S. Kucera et al., Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion, Int. J. Pharm. 271 (1-2), 77-84 (2004).
8. M. M. Crowley, F. Zhang, J. J. Koleng, J. W. McGinity, Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion, Biomaterials, 23(21), 4241-4248 (2002).
9. J. Mc Ginity, F. Zhang, World Patent No. 9749384 (1997).10. F. Zhang, J. W. McGinity, Properties of sustained-release tablets prepared by
hot-melt extrusion, Pharm. Dev. Tech., 4(2), 241-250 (1999).11. F. Zhang, J. W. McGinity, Properties of hot-melt extruded theophylline tablets
containing poly(vinyl acetate), Drug Dev. Ind. Pharm., 26(9), 931-942 (2000).12. C. Aitken-Nichol, F. Zhang, J. W. McGinity, Hot melt extrusion of acrylic fi lms,
Pharm. Res., 13(5), 804-808 (1996).13. M. Munjal, S. P. Stodghill, M. A. Elsohly, M. A. Repka, Polymeric systems
for amorphous D9-tetrahydrocannabinol produced by a hot-melt method. Part I: chemical and thermal stability during processing, J. Pharm. Sci., 1841-1853 (2006).
14. S. Prodduturi, R. V. Manek, W. M. Kolling, S. P. Stodghill, M. A. Repka, Solidstate stability and characterization of hot-melt extruded poly(ethylene oxide) fi lms, J. Pharm. Sci., 94(10), 2232-2245 (2005).
15. M. A. Repka, T. G. Gerding, S. L. Repka, J. W. McGinity, Infl uence of plasticizers and drugs on the physical-mechanical properties of hydroxypropylcellulose fi lms prepared by hot-melt extrusion, Drug. Dev. Ind. Pharm., 25(5), 625-633 (1999).
16. M. A. Repka, J. W. McGinity, Physical-mechanical, moisture absorption and bioadhesive properties of hydroxypropylcellulose hot-melt extruded fi lms, Bio-materials, 21(14), 1509-1517 (2000).
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10210_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:102 27.10.2010 16:14:41 Uhr27.10.2010 16:14:41 Uhr
103
17. M. A. Repka, J. W. McGinity, Bioadhesive properties of hydroxypropylcellulose topi-cal fi lms produced by hot-melt extrusion, J. Contr. Release, 70(3), 341-351 (2001).
18. M. A. Repka, J. W. McGinity, Infl uence of chlorpheniramine maleate on topical fi lms produced by hot-melt extrusion, Pharma. Dev. Tech., 6(3), 295-302 (2001).
19. M. A. Repka, J. O´haver, C. H. See, K. Gutta, M. Munjal, Nail morphology studies as assessment for onychomycosis treatment modalities, Int. J. Pharm., 245, 25-36 (2002).
20. M. A. Repka, S. L. Repka, J. W. McGinity, United States Patent No. 6,375,963 B1 (2002).
21. R. Bhardwaj, J. Blanchard, In vitro evaluation of poly(D,L-lactide-co-glycolide) polymer-based implants containing the alpha-melanocyte stimulating hormone analog, melanotan-I, J. Contr. Release, 45(1), 49-55 (1997).
22. R. Bhardwaj, J. Blanchard, In vitro characterization and in vivo release pro-fi le of a poly(D,L-lactide-co-glycolide)-based implant delivery system for the alpha-msh analog, melanotan.I, Int. J. Pharm., 170(1), 109-117 (1998).
23. A. Rothen-Weinhold, N. Oudry, K. Schwach-Abdellaoui, S. Frutiger-Hughes, G. J. Hughes, D. Jeannerat, et al., Formation of peptide impurities in polyester matrices during implant manufacturing, Eur. J. Pharm. Biopharm., 49(3), 253-257 (2000).
24. A. P. Sam, Controlled release contraceptive devices – A status report, J. Control. Release, 22(1), 35-46 (1992).
25. M. M. Crowley, F. Zhang, M. A. Repka, S. Thumma, S. B. Upadhye, S. K. Battu et al., Pharmaceutical applications of hot-melt extrusion: Part I, Drug Development and Industrial Pharmacy, 33, 909-926 (2007).
26. I. Ghebre-Sellassie, C. Martin, Pharmaceutical Extrusion Technology, Drugs and the Pharmaceutical Sciences, Volume 133 (2007).
27. C. Leuner and J. Dressman, Improving drug solubility for oral delivery using solid dispersions, Eur. J. Pharm. Biopharm. 50, 47-60 (2000).
28. Verein Deutscher Ingenieure (VDI) Kunststofftechnik, Optimierung des Com-poundierprozesses durch Rezeptur- und Verfahrensverständnis, VDI-Verlag GmbH, Düsseldorf (1997)
29. K. Nakamichi, S. Izumi, H. Yasuura, Method of Manufacturing Solid Dispersion, EP 580860 and US 5456923
30. J. Breitenbach, W. Schrof, J. Neumann, Confocal Raman-spectroscopy: Analytical approach to solid dispersions and mapping of drugs, Pharm. Res., 16 (7), 1109-1113 (1999)
31. M. Crowley et al, Pharmaceutical applications of hot-melt extrusion: part I, Drug Dev. Ind. Pharm. 33, 909-926 (2007).
32. A. Foster, J. Hempenstall, T. Rades, Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers, J. Pharm. Pharmacology 53, 303-315 (2001).
33. A. Forster, J. Hempenstall, I. Tucker, T. Rades, Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis, Int. J. Pharm. 226, 147-161 (2001).
10
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10310_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:103 27.10.2010 16:14:41 Uhr27.10.2010 16:14:41 Uhr
104
34. J. E. Patterson, M. B. James, A. H. Forster, T. Rades, Melt extrusion and spray drying of carbamazepine and dipyridamole with polyvinylpyrrolidone / vinylacetate copolymers; Drug Dev. Ind. Pharm 34, 95-106 (2008).
35. S. Janssens, H. Novoa de Armas, J. P. Remon, G. Van den Mooter, The use of a new hydrophilic polymer, Kollicoat IR, in the formulation of solid dispersions of itraconazole, Eur. J. Pharm. Sci. 30, 288-294 (2007).
S. Janssens, G. Van den Mooter, Enhancing solubility and dissolution rate of poorly soluble drugs, WO 2007/115381
36. E. Karavas, G. Ktistis, A. Xenakis, E. Georgarakis, Effect of hydrogen bonding interactions on the release mechanism of felodipine from nanodispersions with polyvinylpyrrolidone, Eur. J. of Pharm. Biopharm. 63, 103-114 (2006).
37. R. J. Chokshi, H. K. Sandhu, R. M. Iyer, N. H. Shaw, A. W. Malick, H. Zia, Cha-racterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot melt extrusion processes as a means to manufac-ture solid dispersion / solution, J. Pharm Sci. 94(11, 2463-2474 (2005).
38. A. Ghebremeskel, C. Vemavarapu, M. Lodaya, Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API, Int. J. Pharm. 328, 119-129 (2007).
39. J. Breitenbach, Melt extrusion: From process to drug delivery technology, Eur. J. Pharm. Biopharm., 54, 107-117 (2002).
40. M. Adel El-Egakey, M. Soliva, P. Speiser, Hot extruded dosage forms Part I, Pharm. Act. Helva (46), 31–52 (1971).
41. H. Hüttenrauch, Spritzgiebverfahren zur Herstellung peroraler Retardpräparate, Pharmazie 29, 297–302 (1974).
42. G. Cuff, F. Raouf, A preliminary evaluation of injection moulding as a technology to produce tablets, Pharm. Technol. 6, 96–106 (1998).
43. C. M. Vaz, P. F. N. M. van Doeveren, R. L. Reis, A. M. Cunha, Soy matrix drug delivery systems obtained by melt-processing techniques, Biomacromolecules 4, 1520–1529 (2003).
44. C. M. Vaz, P. F. N. M. van Doeveren, R. L. Reis, A. M. Cunha, Development and design of double-layer co-injection moulded soy protein based drug delivery devices, Polymer 44, 5983–5992 (2003).
45. L. Eith, R. F. T. Stepto, I. Tomka, F. Wittwer, The injection-moulded capsule, Drug Dev. Ind. Pharm. 12, 2113–2126 (1986).
46. D. Bar-Shalom, L. Slot, W. W. Lee, C. G. Wilson, Development of the Egalet Technology, in: M. J. Rathbone, J. Hadgraft, M. S. Roberts (Eds.), Modifi ed-Release Drug Delivery Technology, Marcel Dekker, New York (2003).
47. C. Vervaet, E. Verhoeven, T. Quinten, J. P. Remon, Hot melt extrusion and injec-tion moulding as manufacturing tools for controlled release formulations, DOSIS 24-2, 119-123 (2008).
48. T. Quinten a, T. De Beer b, C. Vervaet a,*, J. P. Remon, Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets, Eur J. of Pharm. and Biopharm. 71, 145–154 (2009).
49. V. Bühler, Kollidon®: Polyvinylpyrrolidone excipients for the pharmaceutical industry, BASF SE, 9th revised edition (2008)
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10410_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:104 27.10.2010 16:14:42 Uhr27.10.2010 16:14:42 Uhr
105
50. V. Bühler, Kollicoat® Grades: Functional polymers for the pharmaceutical industry, BASF SE (2007).
51. V. Bühler, Pharmaceutical technology of BASF excipients, BASF SE, 3rd revised edition (2008).
52. A. Maschke et al., Effect of preparation method on release behavior of Kollidon® SR tablets hot melt extrusion versus direct compression, Poster, 36th Annual Mee-ting and Exposition of the Controlled Release Society, Copenhagen (2009)
53. D. Djuric et al., Modifi ed release of poorly soluble itraconazole by means of polymer combinations for hot melt extrusion, Poster, AAPS Annual Meeting, New Orleans (2010)
54. S. Janssens, G. Van Den Mooter, Preparation method for solid dispersions, WO 2009 / 118356
55. S. Thumma, M. A. ElSohly, S. Q. Zhang, W. Gul, M. A. Repka, Eur. J. of Pharm. and Biopharm. (70) 2, 605-614 (2005).
56. A. Forster, J. Hempenstall, I. Tucker, T. Rades, Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis, Int. J. Pharm. 226, 147-161 (2001).
57. J. Breitkreutz, Prediction of intestinal drug absorption properties by three-dimensional solubility parameters, Pharm. Res., 15, 1370-1375 (1998).
58. R. F. Fedors, A method for estimating both the solubility parameters and molar volumes of liquids, Pol. Eng. Sci., 14, 147-154 (1974).
59. D. W. Van Krevelen, P. J. Hoftyzer, Properties of polymers. Their estimation and correlation with chemical structures, Amsterdam: Elsevier (1976).
60. R. Gröning, F. J. Braun, Threedimensional solubility parameters and their use in characterizing the permeation of drugs through the skin, Pharmazie, 51, 337-341 (1996).
61. J. Albers, P. Kleinebudde, Hot-melt extrusion with poorly soluble drugs, Dissertation (2008).
10
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10510_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:105 27.10.2010 16:14:42 Uhr27.10.2010 16:14:42 Uhr
106
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10610_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:106 27.10.2010 16:14:42 Uhr27.10.2010 16:14:42 Uhr
107
NoteThis document, or any answer or information provided herein by BASF, does not constitute a legally binding obligation on the part of BASF. While the descriptions, de-signs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may af-fect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. No warranties of any kind either express or implied, including warranties of merchantability or fi tness for a particular purpose are made regarding products described or designs, data or information set forth, or that the products, designs, data or information may be used without infringing the intellec-tual property rights of others. In no case shall the descriptions, information, data or designs provided be considered a part of our terms and conditions of sale.
October 2010
10
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10710_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:107 27.10.2010 16:14:42 Uhr27.10.2010 16:14:42 Uhr
108
Active pharmaceutical ingredients 47-48, 79API solubility 8, 21, 51Appearance polymer extrudates 58-61Appearance polymer mixtures 78Appearance polymer-plasticizer extrudates 68-73
Barrel 9-10, 16, 23, 97, 98Bioavailability 8, 20-21, 27, 32, 92
Carbamazepine 47-48, 51-52, 54-55, 79-82, 84-88, 104 Cinnarizine 51-52Clotrimazole 51-52Conveying elements 13, 97-98Copovidone 19, 24Co-rotating 11, 56, 94Counter-rotating 11Cremophor® RH 40 24, 32-34, 37, 46-47, 53, 66-73, 100
Danazol 51-52Decomposition (GPC) Kollidon® VA 64 63-64Decomposition (GPC) Soluplus® 63, 65Die 9-11, 14-16, 98Differential Scanning Calorimetry (DSC) 34-40, 49, 71-73, 83Dissolution characteristic polymer extrudates 62Dissolution rate 21, 90, 94, 104Downstream processing 15, 42, 68, 78Drug delivery system 8, 17-18, 21, 23, 25Drug release 8, 21, 23, 90-92
Electrostatic charge on the substances 97Estradiol 51-52Ethylene glycol and vinyl alcohol graft copolymer 24Extruder equipment 9, 83Extrusion process 8-23, 34, 39, 41, 49, 63, 79, 94, 96-99Extrusion temperature range polymer mixtures 74-77Extrusion temperature range polymer-plasticizer combinations 66-68Extrusion temperature range polymers 56-57
Feeder 9, 14, 66, 83, 97Feed rate 11, 14, 16-17, 96-98Feeding section 9, 13, 16, 97Fenofi brate 47-48, 51-52, 54-55, 79-81
11 Alphabetical Index
A
B
C
D
E
F
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10810_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:108 27.10.2010 16:14:42 Uhr27.10.2010 16:14:42 Uhr
109
Film casting 35, 70-71, 79-80, 87-89Final dosage form 94-95
Gel Permeation Chromatography (GPC) 63Glass transition temperature 8, 19-20, 34-40, 46, 95-96, 98Gravimetric feeding 14, 97Griseofulvin 51-52
Hot-Melt Extrusion (HME) 8-24, 26, 29, 32, 34-35, 39, 41, 49, 56-57, 63, 71, 74, 79, 82, 87, 95-96
In-vitro characteristics HME formulations 90, 92-93In-vivo characteristics HME formulations 90, 92-93Injection molding 22-23Itraconazole 47, 51-52, 54-55, 79-93
Ketoconazole 51-52Kneading elements 12-14, 97-98Kollicoat® IR 16, 18, 20, 24, 29-31, 37-39, 42, 46, 49, 52, 54, 56-57, 60-62, 66-71, 74-76, 78-79, 81-82, 85-89, 91, 100-101 Kollicoat® MAE 100P 18, 24, 29, 49, 54, 56-57, 70-71, 85Kollicoat® Protect 18, 24, 29-31, 49, 54, 56-57, 60-62, 66, 69-71, 79, 81-82, 85-86, 88Kollidon® 12 PF 24, 27, 42, 46, 49, 54, 56-57, 59, 61-62, 66, 69-71, 79, 81-82, 84, 86Kollidon® 17 PF 24, 27, 42, 49, 52, 54, 56-57, 59, 61-62, 66, 71, 79, 81-82, 84, 86, 88Kollidon® 30 20, 24, 27, 37, 39-40, 42, 49, 54, 56-57, 70-71, 74-76, 78-79, 82, 84, 86, 88, 100-101Kollidon® 90 F 24, 27, 37, 39-40, 42, 49, 54, 56-57, 70-71, 74-75, 77-79, 82, 85-86, 88, 91Kollidon® CL 94Kollidon® SR 18, 24, 28, 36-38, 49, 52, 54, 56-57, 59, 61-62, 66, 69-71, 74-75, 78-79, 81-82, 85-86, 90Kollidon® VA 64 16, 18, 20-21, 24-25, 35, 37-40, 42, 44, 46, 49, 51-52, 54, 56-58, 61-64, 66, 69, 79, 81-85, 86, 88, 91, 100
Lµtrol® micro 68 24, 31-32Lµtrol® micro 127 24, 31-32Lutrol® F 68 24, 31-32, 37, 44, 46, 55, 66-72, 100Lutrol® F 127 24, 31-32, 34, 42-43, 46, 49, 54, 56-57, 60-62, 70, 79, 82, 85-86, 88, 90, 100
G
H
I
K
L
11
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:10910_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:109 27.10.2010 16:14:43 Uhr27.10.2010 16:14:43 Uhr
110
Macrogolglycerol hydroxystearate 40 24, 32Macrogol polyvinyl alcohol grafted co-polymer 24Macrogol polyvinyl alcohol grafted copolymer + poly(vinyl alcohol) 24Macrogols 24Melt viscosity 11, 17, 20, 34, 40-44, 56-57, 96, 98Melting point 34-35, 38, 71-72, 96Melting zone 9-10Methacrylic acid copolymer type C 24Methacrylic acid - ethacrylate copolymer 1:1 24 Miscibility polymer-plasticizer combinations 70-73Mixing zone 10, 98
PEG 1500 37, 44, 46, 51-52, 55, 66, 68-73, 81-82, 84-86, 88, 100Pelletizing characteristic polymer extrudates 58-61Pelletizing characteristic polymer mixtures extrudates 78Pelletizing characteristic polymer-plasticizer extrudates 68-69Pelletizing device 15Piroxicam 51-52Plasticizer 20, 24, 32-37, 44, 46-47, 50, 53-56, 62, 66, 68-71, 74, 80-82, 84, 90, 100Poloxamers 31-32, 35Polyethylene glycols 24, 33, 100Polymer characteristic for HME 19Polyoxyl hydrogenated castor oil 24Polyvinyl acetate 25-26, 28, 62, 66, 100Povidones 57Practical recommendation 96Process variables 16
Regulatory aspects 100Residence time 11, 14, 16-17, 96
Sampling 99Screw confi guration 12, 14, 35, 49, 97-98Screw speed 11, 14, 16-17, 37, 56, 66, 70, 74, 96, 98Segregation of blends 97Shaping section 9Single-screw extruder 11-12Solid dispersion 17-18, 32, 82, 90Solid solution 8, 17, 20-22, 27, 79-80, 86-87, 92-94Solubility parameter 7, 19-20, 53-55Solubilization capability 20Solubilization capacity by fi lm casting 80-81, 87-89Solubilization capacity by HME 84-87
P
R
S
M
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:11010_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:110 27.10.2010 16:14:43 Uhr27.10.2010 16:14:43 Uhr
111
T
V
X
Soluplus® 18-20, 24, 26-27, 35, 37-40, 42, 45-46, 49, 51-52, 54, 56-58, 60-66, 69-71, 74-76, 78-79, 81-82, 84, 86, 90, 92-93, 101Specifi c heat capacity 49-50Stability of solid dispersions 82-85
Thermal Gravimetric Analysis (TGA) 45-48, 57, 63Torque 11, 15, 17, 42, 96Twin-screw extruder 11-12, 16, 82, 97-98
Volumetric feeding 10, 14
X-ray Diffraction (XRD) 82-85, 88-89
Gesamtherstellung: Servicecenter Medien und Kommunikation
11
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:11110_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:111 27.10.2010 16:14:43 Uhr27.10.2010 16:14:43 Uhr
112
Regional Contact
AsiaBASF East Asia Regional Headquarters Ltd.Sharon LimPhone: +852 (27 31) 70 [email protected]
EuropeBASF SESilke WerthPhone: +49 (621) 607 69 [email protected]
North AmericaBASF CorporationSuzanna BrownPhone: +1 (973) 245 63 [email protected]
South AmericaBASF S. A.Flavia de Assis e SouzaPhone +55 11 (30 43) 22 37fl [email protected]
10_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:11210_P_0380_BASF_Buch_HotMelt_80_112.indd Abs1:112 27.10.2010 16:14:43 Uhr27.10.2010 16:14:43 Uhr
Hot-Melt Extrusion with BASF Pharma PolymersExtrusion Compendium K. Kolter, M. Karl, S. Nalawade, N. Rottmann
This book is intended for pharmaceutical technologists who are already, or are considering, working with hot-melt extrusion.
The relevant properties of the various BASF pharma polymers, plasti-cizers and solubilizers intended for use in hot-melt extrusion as well as combinations of these are described in detail.
Furthermore, information is provided on how to process actives in hot-melt extrusion, how to characterize the resulting formulations and how to develop stable drug delivery systems. Practical recommendations for applications involving hot-melt extrusion are also given.
BASF_Buch_HotMelt_Buchdecke_Vorab_148x230.indd 2BASF_Buch_HotMelt_Buchdecke_Vorab_148x230.indd 2 27.10.2010 15:59:03 Uhr27.10.2010 15:59:03 Uhr