GENPMD318 Hot Melt Extrusion with BASF Pharma Polymerss3.amazonaws.com/zanran_storage/… · ... the drug delivery ... [5, 6], sustained release tablets [7, 8, 9, 10, 11], transdermal

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


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


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


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


6


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.


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


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


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)


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


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].


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


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)


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


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


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


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


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


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.


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


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.


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.


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


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


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® [%

]


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


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


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


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.


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


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


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


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


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


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


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


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.


T g/T m

* [°

C]


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


T g [°C

]


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

]


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


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.


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


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.


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


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.


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


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


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


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


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


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


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


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


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


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


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


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.


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


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.


61

PolymerProcessing Temperature [°C]

Characteristics Pure Polymer

Kollidon® VA 64 150 Appearance: Clear

Pelletizing: + (Regular pellets)

Soluplus® 120 Appearance: Clear


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


Kollicoat® IR 160 Appearance: Quite clear


Kollicoat® Protect 160 Appearance: Quite clear to cloudy


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


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.


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


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.


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


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.


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


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.


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


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


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


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


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


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.


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]


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


T pr

oces

sing

[°C]


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]


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


T pr

oces

sing

[°C]


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


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


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


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


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


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


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


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 (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 %


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




Extrudates (3 months) 20 % 45 %

Kollicoat® MAE 100P + 10 % PEG 1500

Process temperature Not processable!

Kollicoat® IR + 10 % PEG 1500


Extrudates (initial value) <20 % 25 %



Kollicoat® Protect + 10 % PEG 1500

Process temperature 140 °C 145-150 °C

Extrudates (initial value) <10 % <20 %



Lutrol® F 127


Extrudates (initial value) 30 % <15 %



4


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.


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)


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


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.


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


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


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.


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


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.


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


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)


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


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.


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


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.


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


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


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


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).


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


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)


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


106


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


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


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


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


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


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]


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

Documents

GENPMD318 Hot Melt Extrusion with BASF Pharma Polymerss3.amazonaws.com/zanran_storage/… · ... the drug delivery ... [5, 6], sustained release tablets [7, 8, 9, 10, 11], transdermal