European Journal of Pharmaceutics and Biopharmaceutics 49 (2000) 237–242
`
`Research paper
`Melt extrusion – an alternative method for enhancing the dissolution rate
`of 17b-estradiol hemihydrate
`
`www.elsevier.com/locate/ejphabio
`
`S. Hu¨lsmanna, b,*, T. Backensfelda, S. Keitela, R. Bodmeierb
`
`aPharmaceutical Development/Oral Dosage Forms, Schering AG, Berlin, Germany
`bCollege of Pharmacy, Freie Universita¨t Berlin, Berlin, Germany
`
`Received 4 May 1999; accepted in revised form 9 February 2000
`
`Abstract
`
`17b-Estradiol hemihydrate (17b-E2) is a poorly water-soluble drug. Physical methods for improving the solubility and dissolution rate,
`e.g. micronization, have certain inherent disadvantages. The method of choice in this study, melt extrusion, proved to overcome many of the
`shortcomings of conventional methods. Different compositions of excipients such as PEG 6000, PVP (Kollidonw 30) or a vinylpyrrolidone-
`vinylacetate-copolymer (Kollidonw VA64) were used as polymers and Sucroesterw WE15 or Gelucirew 44/14 as additives during melt
`extrusion. The solid dispersions resulted in a significant increase in dissolution rate when compared to the pure drug or to the physical
`mixtures. For example, a 30-fold increase in dissolution rate was obtained for a formulation containing 10% 17b-E2, 50% PVP and 40%
`Gelucirew 44/14. The solid dispersions were then processed into tablets. The improvement in the dissolution behavior was also maintained
`with the tablets. The USP XXIII requirement for estradiol tablets reaching greater than 75% drug dissolved after 60 min was obtained in this
`investigation. q 2000 Elsevier Science B.V. All rights reserved.
`
`Keywords: Solid dispersions; Melt extrusion; Tablets; 17b-Estradiol hemihydrate; Polymers; Poorly soluble drugs
`
`1. Introduction
`
`Physical methods for enhancing the dissolution rate of a
`sparingly water soluble drug, such as micronization, or
`traditional methods for the preparation of solid dispersions,
`such as the melt or solvent method, have several disadvan-
`tages.
`to handle
`Micronized powders/drugs can be difficult
`because of air adsorption, high dust formation and low
`apparent densities. Lin et al. reported that although a reduc-
`tion in particle size may be easy, the anticipated increase in
`bioavailability may not be achieved because of aggregation
`or agglomeration resulting in poor powder wettability [1].
`The preparation of solid dispersions by melt or solvent
`methods is an alternative way to enhance the solubility of a
`sparingly water soluble drug. This concept was introduced
`by Sekiguchi and Obi [2] and has been studied and reviewed
`extensively [3–5]. The melt method often requires relatively
`high temperatures (more than 1008C), which may lead to
`thermal degradation of the drug. Problems with the solvent
`
`* Corresponding author. Schering AG, Endfertigung Charlottenburg,
`Betriebsleitung C3, Max-Dohrn-Straße 8, 10589 Berlin. Tel.: 149-30-
`4681-6486; fax: 149-30-4681-6114.
`E-mail address: stefan.huelsmann@schering.de (S. Hu¨lsmann)
`
`method include environmental aspects due to the use of
`organic solvents and health concerns because of residual
`solvents. In addition, solvent methods are time-consuming
`and expensive because of long processing and drying times.
`The use of polymers for the manufacture of solid disper-
`sions, such as PEG 6000, PVP or PVA 64 [6], have been
`described comprehensively. Additives like Geluciresw [7,8]
`or Sucroesterw [9,10] have been used recently to improve
`the dissolution behavior of model compounds. To date, few
`formulations have been described utilizing polymers and
`additives as excipients.
`The objective of this study was to investigate the melt
`extrusion technique using polymers and additives to prepare
`solid dispersions in order to enhance the drug dissolution
`rate of the model drug, 17b-E2 as an alternative to the
`traditional methods. Melt extrusion has been described
`primarily as a method for the preparation of sustained
`release preparations [7,11,12], but not for the enhancement
`of the dissolution rate.
`In addition, only limited information is available on the
`processability of solid solutions/dispersions into the final
`dosage form. Special emphasis was, therefore, placed on
`the development of a single unit dosage form (e.g. tablets)
`taking into consideration industrial requirements, such as
`
`0939-6411/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
`PII: S 0 9 3 9 - 6 4 1 1 ( 0 0 ) 0 0 0 7 7 - 1
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`238
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`
`mortar and pestle and the particle size fraction of ,0.1 mm
`and .0.4 mm was used for further experimentation.
`The formulations of the melt-extruded solid dispersions
`are shown in Table 1. Physical mixtures containing the same
`ratio of carrier and drug as the melt-extruded batches were
`prepared for comparison.
`
`2.3. Preparation of the tablets
`
`Eighty milligram tablets each containing 2 mg 17b-E2
`were prepared on an instrumented single punch press (EK0,
`Korsch, Berlin, Germany) with 6 mm punches. The
`extruded solid dispersions were crushed with a mortar and
`pestle and sieved (B 0.315 mm), as were the other excipi-
`ents (microcrystalline cellulose, corn starch and magnesium
`stearate). All ingredients of the tablet formulation except
`magnesium stearate were mixed for 15 min at 400 rev./
`min in a ploughshear blender (MTI Type M3, Lage,
`Germany). After the addition of magnesium stearate, the
`blend was mixed again for 1 min at 400 rev./min.
`A typical tablet formulation containing 2 mg 17b-E2
`consisted of 8.3% solid dispersion, 45.6% microcrystalline
`cellulose, 45.6% corn starch and 0.5% magnesium stearate.
`The tablet hardness was determined by diametrical
`compression on a motorized tablet hardness tester (Model
`6D; Schleuniger, Jugenheim, Switzerland). The target tablet
`hardness was 50 N.
`
`2.4. Dissolution tests
`
`In vitro dissolution studies on tablets or bulk solid disper-
`sion containing 2 mg of 17b-E2 were performed using the
`USP XXIII paddle dissolution apparatus (Dissolutiontester
`CD6, Janke und Kunkel, Staufen i.Br., Germany) with either
`900 ml 0.1 N HCl or 500 ml 0.3% sodium dodecyl sulfate
`aqueous solution, 100 rpm, and at 37 ^ 0:58C in triplicate.
`Samples were withdrawn after 5, 10, 30 and 60 min, filtered
`(B 0.45 mm, regenerated cellulose) and assayed using a
`validated HPLC method at 242 nm (Gynkotek GINA 160,
`UVD 160, Germering, Germany) with a C18-reversed phase
`column and a mixture of acetonitrile, water, methanol and
`tetrahydrofuran as mobile phase. Data acquisition and
`evaluation was performed with the Access*Chrom software
`package (PE Nelson, Cupertino, USA). Although sink
`conditions could only be maintained in the dissolution
`experiments with 0.3% SDS, nevertheless, HCl was used
`
`Table 1
`Composition of the melt-extruded solid dispersions
`
`Drug or excipient
`
`Composition of the
`solid dispersion
`
`17b-Estradiol-hemihydrate
`Polymer (PEG 6000, PVP, PVA 64)
`Additive (Sucroesterw WE15, Gelucirew 44/14)
`
`10 or 30%
`50 or 30%
`40%
`
`Fig. 1. Schematic of a single screw melt extruder.
`
`easy and fast handling, while avoiding organic solvents and
`thermal stress on the drug.
`
`2. Materials and methods
`
`2.1. Materials
`
`17b-E2 (Schering AG, Berlin/Bergkamen, Germany;
`non-micronized with a mean diameter of 187 mm, data for
`the water solubility of Estradiol (0.2–5 mg/ml) were taken
`from the literature [13,14], the solubility of the drug in 0.3%
`SDS is about 60 mg/ml), PEG 6000, PVP (Kollidonw 30:
`vinylpyrrolidone, PVA 64 (Kollidonw VA64, vinylpyrroli-
`done/vinylacetate–Copolymer 6:4) (BASF AG, Ludwigsha-
`Sucroesterw WE15
`(saccharose-
`fen,
`Germany),
`monopalmitate, HLB value of 15, melting point 608C),
`Gelucirew 44/14 (mixture of 30% glycerolester and 70%
`PEG-ester with fatty acids; the first number in the designa-
`tion of a Gelucirew product indicates its melting point, the
`(Gattefosse´, Weil am Rhein,
`second its HLB value)
`Germany), microcrystalline cellulose (Avicelw PH101,
`FMC, Philadelphia, USA), corn starch (Roquette, Lestrem,
`France) and magnesium stearate (Faci Carasco, Italy).
`
`2.2. Melt extrusion
`
`An 18-mm single screw (metal, 30 cm, stepwise reduc-
`tion of threads) extruder with a single rod die (Allrounder
`100U, Arburg, Loßburg, Germany) was employed for carry-
`ing out the melt extrusion. It has three heating zones (two
`cylinder heating zones and one die heating zone), where
`only the middle zone was used (Fig. 1).
`The drug and excipients were mixed using a mortar and
`pestle, even the treatment of Gelucirew was possible. The
`middle heating zone was heated to 608C, while the mixing
`zone was cooled by water. The extrusion temperature was
`well below the drug’s melting point of 1758C and also below
`its decomposition temperature. Once the extrusion tempera-
`ture was reached, the melt extrusion with a screw rotation of
`50 rev./min was started. The extruded and cooled product
`had a ‘spaghetti-like’ shape and was then crushed with a
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`S. Hu¨lsmann et al. / European Journal of Pharmaceutics and Biopharmaceutics 49 (2000) 237–242
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`239
`
`solubility and/or the rate of dissolution of sparingly water
`soluble drugs. PVP has been reported to prevent possible
`drug recrystallization [15]. The amount of PVP and PVA 64
`in the formulation was limited due to their relatively high
`melting points (.1508C) (formulations B–E) and resulting
`extruder clogging at higher polymer concentrations.
`Low melting additives had to be included in the formula-
`tion in order to facilitate processing. A minimum amount of
`40% additives, which melt at the extrusion temperature of
`608C, was necessary. Sucroesterw WE15 and Gelucirew 44/
`14 were used because of their low melting points (,608C),
`their amphiphilic character and their possible ability to
`prevent drug recrystallization during storage.
`The preparation of melt-extruded solid dispersions
`clearly resulted in an increase in drug release when
`compared to the pure drug (Table 2). A 10–32-fold improve-
`ment in dissolution in 0.1 N HCl was obtained with the melt-
`extruded formulations. Although Sucroesterw WE15 had an
`advantageous influence on the drug dissolution, its effect
`was less when compared to the other additives. The batch
`with 90% Sucroesterw (formulation H) led to only a 10-fold
`increase in dissolution after 60 min and could not reach the
`results obtained from the other batches containing Sucroes-
`terw WE15 in combination with a polymer (formulations C,
`E and G). Because of its low melting point (448C) and pasty
`character, Gelucirew; 44/14 could not be used by itself, but
`only in combination with a polymer (formulations B, D and
`F).
`The effect of different polymers (PEG 6000, PVP, PVA
`64) on the release of 17b-E2 from solid dispersions contain-
`ing 10% 17b-E2, 40% Gelucirew 44/14 and 50% polymer
`(formulations B, D and F) is illustrated in Fig. 3. PVP exhib-
`ited the best dissolution enhancement and was, therefore,
`selected as the polymer for the preparation of tablets. The
`dissolution of 17b-estradiol in PVP is probably better than
`its dissolution in the other polymers.
`
`Table 2
`Amount of 17b-E2 dissolved after 60 min in 900 ml 0.1 N HCl from
`different melt-extruded formulations
`
`Formulation
`
`% 17b-E2
`dissolved
`
`Standard
`deviation (%)
`
`Fig. 2. Dissolution of a melt extruded solid dispersion and pure 17b-E2
`(dissolution media: 0.1 N HCl).
`
`as discriminating dissolution medium, since differences
`could be recognized in a better way.
`
`2.5. X-ray powder diffraction (XRPD)
`
`Data collection was carried out in transmission mode on
`an automated STOE Powder Diffractometer STADIP
`(STOE, USA) using germanium-monocromatized CuKa1-
`radiation (l(cid:136) 1:5405989 A˚ ). The X-ray tube with a copper
`anode was operated at 40 kV and 30 mA. The 2u scans were
`performed using the small linear position sensitive detector
`with an angular resolution of 0.088 between 38 #2 u # 408
`(stepwidth 18). The samples were enclosed between two
`polyacetate films held together by double sided adhesive
`tape. Data acquisition and evaluation was performed using
`the version 2.75 of the Stoe Visual-Xpow software package.
`
`3. Results and discussion
`
`Before determining the dissolution rate of the different
`batches, the content of 17b-estradiol in each melt extruded
`batch was assayed by the same HPLC method as was used
`for the dissolution test. The assay values were between 95
`and 100% of theoretical. No additional peak, indicating
`decomposition, appeared.
`The amount of drug release in 0.1 N HCl from a solid
`dispersion containing 10% 17b-E2, 50% PVP and 40%
`Gelucirew 44/14 was significantly higher when compared
`to the pure, non-micronized drug (Fig. 2). While less than
`2% of the non-micronized drug was dissolved after 60 min,
`about 57% of the drug was released from the solid disper-
`sion. This is approximately a 32-fold difference between the
`two formulations. The importance of the choice of carrier
`materials on the performance of solid dispersions has been
`reported extensively [4,5]. Polymers primarily enhance the
`
`C
`
`A 17b-E2
`10% 17b-E2, 50% PVP, 40%
`B
`Gelucirew 44/14
`10% 17b-E2, 50%, PVP 40%
`Sucroesterw WE15
`D 10% 17b-E2, 50% PVA 64,
`40% Gelucirew 44/14
`10% 17b-E2, 50% PVA 64,
`40% Sucroesterw WE15
`10% 17b-E2, 50% PEG 6000,
`40% Gelucirew 44/14
`G 10% 17b-E2, 50% PEG 6000,
`40% Sucroesterw WE15
`H 10% 17b-E2, 90%
`Sucroesterw WE15
`
`E
`
`F
`
`1.8
`57.2
`
`39.7
`
`37.7
`
`32.0
`
`38.1
`
`38.7
`
`17.3
`
`1.6
`1.8
`
`3.4
`
`0.7
`
`2.6
`
`2.1
`
`1.8
`
`1.9
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`
`Fig. 3. Effect of polymer on the dissolution behavior (dissolution media:
`0.1 N HCl).
`
`Fig. 5. Comparison of a melt extruded solid dispersion with a physical
`mixture and pure 17b-E2 (dissolution media: 0.1 N HCl).
`
`In order to investigate the effect of particle size on disso-
`lution behavior of the solid dispersion (formulation G), the
`melt extrudate was ground with a mortar and pestle and
`sieved into two different fractions (e.g. .0.4 mm, ,0.1
`mm). Although the smaller size fraction (,0.1 mm) had a
`higher initial dissolution rate, particle size of the solid
`dispersion had only a minor influence on the amount of
`drug released after 1 h (Fig. 4). These results suggest that
`the drug was homogeneously dispersed in the carrier. The
`dissolution of the drug from the solid dispersion was not
`only higher than the dissolution of the pure, non-micronized
`drug but was also higher than the release from a physical
`mixture (Fig. 5). The physical mixture was prepared by
`intimately mixing the drug and the excipients with a mortar
`and pestle. Comparing the dissolution profile of a physical
`
`Fig. 4. Effect of particle size of the solid dispersion on the drug release
`(dissolution media: 0.1 N HCl).
`
`mixture vs. the melt extruded solid dispersion, 16% 17b-E2
`was released from the physical mixture after 60 min while
`almost 40% was released from the solid dispersion. The
`release from the physical mixture was also faster than the
`dissolution of the pure drug, possibly due to improved
`wetting of the drug particles.
`These results suggest that melt extrusion is a suitable
`process for the preparation of solid dispersions and for the
`enhancement of the dissolution of a poorly water soluble
`drug.
`theories have been proposed to explain the
`Several
`enhancement in dissolution rate from solid dispersions.
`Corrigan proposed that
`the increase in dissolution rate
`resulted from the formation of high energy, metastable,
`amorphous phases [16]. This theory could not be applied
`in the present system. The X-ray diffraction pattern of the
`pure drug and the solid dispersion indicated that there was
`crystalline 17b-E2 in the melt extruded material (Fig. 6).
`Better results concerning the dissolution rate may be
`expected with amorphous material. However, problems
`concerning stability might be reduced, since recrystalliza-
`tion may be minimal. Some additional peaks were observed
`with the melt extruded batch, which could be assigned to
`Sucroesterw WE15.
`The reason for the higher dissolution rates in this study
`was probably the improved wettability of the drug [17]. In
`contrast to the physical mixture, the dispersed drug particles
`in the solid dispersion are surrounded by the water-soluble
`carrier polymer, and also by amphiphilic additives facilitat-
`ing drug release. The polymer/additives dissolve/disperse
`readily in contact with the release medium and therefore
`result
`in a better wetting of the drug particles by the
`medium. Therefore, melt extrusion leads to a better mixing
`of drug and excipients or a better embedding of the drug in
`the carrier, respectively.
`The melt-extruded dispersions were incorporated into
`tablets as the final dosage form with the objective to eluci-
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`241
`
`the USP requirement of 75%
`the solid dispersion met
`dissolved in 60 min (Fig. 7). The drug dissolution from
`the tablets containing melt-extruded 17b-E2 was also
`compared with a tablet containing the pure drug and the
`same excipients (polymer and low melting additive). An
`increase in drug dissolution from approximately 27% for
`tablets containing pure drug to more than 75% for tablets
`containing the solid dispersions could be demonstrated.
`These results correspond to results which were shown for
`the release from the solid dispersion in comparison to the
`physical mixture (Fig. 5). The release from the melt-
`extruded solid dispersion was not affected by the tabletting
`process, as shown by almost overlapping release curves for
`the powdered melt extrudate and the tabletted melt extru-
`date (Fig. 7). Standard deviations for the melt extruded solid
`dispersion was much higher than for the tablets.
`In conclusion, melt extrusion is a suitable process for the
`preparation of solid dispersions in order to improve the
`dissolution rate of a sparingly water soluble drug. It is an
`attractive alternative to micronization or traditional methods
`for the preparation of solid dispersions, because it is a fast
`and simple one-step-process avoiding the use of organic
`solvents and high production temperatures. The skillful
`choice of excipients, i.e. the combination of polymers and
`additives, can contribute to a more desirable dissolution rate
`profile and the potential of the development of a superior
`single dosage unit.
`
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`Fig. 6. X-ray diffractogram of bulk drug in comparison with a solid disper-
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`
`date whether the enhancement in the dissolution rate could
`be maintained with the tablets. In order to allow the easy
`manufacturing of the tablets, the amount of solid dispersion
`per tablet was reduced by preparing solid dispersions with a
`higher drug loading of 30% 17b-E2 in order to improve
`flowability of the tablet mass and to reach content unifor-
`mity more easily. Before tableting,
`it was assured by
`conducting dissolution tests that there was no difference
`between the 10%- and the 30%- drug-loaded solid disper-
`sions. A content of 8.3% of solid dispersion per 80 mg-tablet
`was sufficient to obtain tablets containing 2 mg 17b-E2.
`Solid dispersions with Gelucirew 44/14 were pasty and
`difficult to handle, especially with regard to the flowability
`of the tablet mass and the uniform filling of the dies. There-
`fore, a solid dispersion with 30% 17b-E2, 30% PVP and
`40% Sucroesterw WE15 as the melting agent was manufac-
`tured.
`The dissolution test was conducted according to the USP
`XXIII monograph for estradiol tablets in 500 ml 0.3%
`sodium dodecyl sulfate in water [18]. All tablets containing
`
`Fig. 7. Drug release from solid dispersions and tablets containing pure drug
`or a solid dispersion (dissolution media: 0.3% aqueous SDS-solution).
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