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Research Paper

Journal of Pharmacy And Pharmacology

Investigation into mixing capability and solid dispersion preparation using the DSM Xplore Pharma Micro Extruder Toshiro Sakaia and Markus Thommesb a Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc., Yaizu, Shizuoka, Japan and bInstitute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf, Germany

Keywords dispersive mixing; distributive mixing; formulation screening; melt extrusion; small scale extruder; solid dispersion Correspondence Toshiro Sakai, Pharmaceutical Research and Development Laboratories, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan. E-mail: [email protected] Received February 21, 2013 Accepted April 16, 2013 doi: 10.1111/jphp.12085

Abstract Objectives The goal of this investigation was to qualify the DSM Xplore Pharma Micro Extruder as a formulation screening tool for early-stage hot-melt extrusion. Methods Dispersive and distributive mixing was investigated using soluplus, copovidone or basic butylated methacrylate copolymer with sodium chloride (NaCl) in a batch size of 5 g. Eleven types of solid dispersions were prepared using various drugs and carriers in batches of 5 g in accordance with the literature. Key findings The dispersive mixing was a function of screw speed and recirculation time and the particle size was remarkably reduced after 1 min of processing, regardless of the polymers. An inverse relationship between the particle size and specific mechanical energy (SME) was also found. The SME values were higher than those in large-scale extruders. After 1 min recirculation at 200 rpm, the uniformity of NaCl content met the criteria of the European Pharmacopoeia, indicating that distributive mixing was achieved in this time. For the solid dispersions preparations, the results from different scanning calorimetry, powder X-ray diffractometry and in-vitro dissolution tests confirmed that all solid-dispersion systems were successfully prepared. Conclusions These findings demonstrated that the extruder is a useful tool to screen solid-dispersion formulations and their material properties on a small scale.

Introduction Solid dispersions are commonly used in pharmaceutics to improve the bioavailability of poorly water-soluble drugs. The generic term ‘solid dispersion’ refers to the definition by Chiou and Riegelman – the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by the melting (fusion) method, solvent method or fusion-solvent method.[1] Since the 1960s, many solid-dispersion formulations have been developed and currently there are seven major types of solid dispersions together with various subtypes.[2,3] These solid dispersion are summarized in Table 1, based on their number of phases and solid-state properties. For the actual production of solid dispersions, solvent methods (such as spray drying) and fusion methods are generally employed, although there are a number of other methods in current use.[2,4] Among the fusion methods, hot-melt extrusion (HME) is a suitable technique for

solid-dispersion preparation because of its ability to intensively mix even highly viscous materials without the need for a solvent. The most common extruder for pharmaceutical HME is a co-rotating twin-screw extruder. This is preferred because of its self-wiping and intensive-mixing capabilities, which are especially helpful when the extruder is only partially loaded.[5] During the extrusion process, active ingredients must be uniformly mixed with the matrix, although the degree of mixing required may depend on the type of solid dispersion, property of components, composition and the Quality Target Product Profile (QTPP). There are two types of mixing to be evaluated – dispersive mixing and distributive mixing.[6] In dispersive mixing, particle size and agglomeration of solid or liquid droplets are reduced. In distributive mixing, repeated re-arrangement of components enhances the system’s homogeneity.

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

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Table 1

Toshiro Sakai and Markus Thommes

Solid dispersion types

Solid dispersion types

Phases

Drug

Carrier

Subtypes

Solid solution

1

Molecularly dispersed

Crystalline

Continuous discontinuous, substitutional discontinuous, interstitional

Glass solution Compound or complex FOrmations

1 1

Molecularly dispersed Molecularly dispersed

Amorphous Amorphous or crystalline

Eutectic mixture Solid crystal suspensions Amorphous precipitation Glass suspensions

2 2 2 2

Crystalline Crystalline Amorphous Crystalline

Crystalline Crystalline Crystalline Amorphous or crystalline

Table 2

Acid-base paired complex inclusion complex co-crystal co-amorphous

Amorphous carrier crystalline carrier

Small-scale extruders

Machine type

Screw diameter (mm)

Screw length (mm)

Throughput

Brabender KETSE 12 DSM Xplore Pharma Micro Extruder DSM Xplore 15 ml Leistritz Nano-16 MP&R ME7.5 Mini-Extruder Rondol Microlab 10 Steer Omicron 12P ThermoScientific HAAKE MiniLab ThermoScientific Pharma 11 HME ThermoScientific Pharma TSG 16 Three-Tec ZE 5 Three-Tec ZE 16

12 5.3–14 9.0–22.4 16 7.5 10 12 5.3–14 11 16 5 16

432 120 170 400 112.5 200–400 288–744 109 440 400 100 512

100–5000 g/h 2 or 5 g/batch, 20–1500 g/h 3, 7 or 15 g/batch, 50–3000 g/h 20–100 g/batch 50–200 g/h 25–400 g/h 200–2000 g/h 10 g/batch 20–2500 g/h pure IND. These results completely followed the results from a pilot-scale extrusion.[29] Compound or complex formations: Co-crystal The CBZ : IND formulation (F7) was processed to prepare the co-crystal. The F7 discharge was a yellowish transparent solution and immediately formed a yellowish white plate on the aluminium pan. A strand-shaped extrudate might be obtained if the barrel temperature was reduced precisely during the process, but this would require a much longer processing time (Figure 2) and could provoke the degradation of CBZ.[26] The melting point (Tm) of the discharged material (162.1°C) was completely different from those of pure CBZ (191.2°C) and NIC (129.1°C). The XPRD pattern showed the existence of a crystalline phase, but the pattern was completely different from those of CBZ or NIC. The dissolution of the milled product was comparable with that of pure NIC, but slightly higher than that of pure CBZ. In the literature, only the results of intrinsic dissolution have been discussed, with the co-crystal showing slightly slower dissolution in comparison with the pure CBZ.[26,30] The difference in the dissolution results between this study and those reported in the literature may be due to the difference in material surface available for the wetting during the dissolution. For intrinsic dissolution, a compressed tablet was made to keep the surface area constant, and the surface was forced to wet at the beginning of the dissolution test using a sinkable tablet holder. In this study, the wetting rate of the test materials should be taken into account because the uncompressed powder materials with larger surface area than the tablet were introduced into the dissolution media, and they must be wetted before dissolution of the drug can occur. This hypothesis is also supported by the fast dissolution of NIC (>95% in 10 min) from the milled co-crystal in this study.

Small-scale HME

Eutectic mixture The eutectic mixture, IBU : PLX formulation (F9) was processed using the pharma micro extruder. The discharge of F9 was a transparent, low-viscosity fluid that spread on the aluminium dish. After cooling it down to 2–8°C in a glass container, it solidified into a white opaque waxy mass. The behaviour of this melt was comparable with that reported in the literature.[31] Since the melt took more than a day to solidify, it was not realistic to obtain a strand-shaped extrudate with this formulation. The DSC results confirmed a single melting point that was lower than the melting point of each crystalline component, and XRPD results showed the existence of two kinds of crystallites. The dissolution rate of the extrudate was remarkably higher than that of either the intact crystalline drug or the physical mixture, in agreement with the findings of Passerini et al. [31] Solid crystal suspension The GFV : MAN formulation (F10) was extruded to prepare a solid crystal suspension. The F10 extrudate was a white, opaque strand with a rough surface, since the die temperature could not be set independently from the barrel temperature. All characterization results, including DSC, XRPD and dissolution, agreed with results reported in the open literature. In addition, it should be noted that the D50 of GFV before and after the extrusion was 42.6 ⫾ 10.6 and 4.1 ⫾ 0.1 mm, respectively. Reitz et al. used a pilot-scale extruder for the same formulation with a D50 of 169 mm for the drug and varied process conditions, and obtained a D50 in the range of 2.3–40.5 mm after the extrusion.[32] The results suggest that the dispersive mixing capability of the pharma micro extruder was comparable with that of pilot-scale extruders when 10 min recirculation was applied. Glass suspensions: Amorphous drug in an amorphous carrier The IND : CA formulation (F11) was processed to manufacture a glass suspension with an amorphous drug in an amorphous carrier. The discharged F11 appeared as a yellowish transparent solution, which solidified immediately on the cooled aluminium pan. The product exhibited a halo pattern in XRPD and two Tg values in DSC, indicating two immiscible amorphous clusters. The Tg values of the extrudate (13.9 and 35.1°C) were between those of the amorphous CA (11.1°C) and amorphous IND (44.2°C). Based on the literature, CA could be dissolved into IND up to 0.25 weight fraction, and above that CA existed separately from IND-CA phase in the amorphous state.[16] The extrudate exhibited a remarkably lower dissolution

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

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rate than that of the physical powder mixture. This result may be explained by the significant retarding effect of CA on IND dissolution when the compounds are in close contact. The CA lowers the pH at the dissolving surface and suppress the release of IND, as suggested in the literature.[33]

NAP–aPMMA clusters might be coated with highly soluble MAN. This result also supports the suggestion that the slower dissolution of NAP–aPMMA was caused not by the wetting or dispersion of the extrudate particles but by the strong interaction between NAP and aPMMA, as suggested in the literature.[28]

Glass suspensions: Crystalline drug in an amorphous carrier

Conclusions

CBZ : SOL (F12), CBZ : aPMMA (F13) and CBZ : COP (F14) at a weight ratio of 70:30 were extruded to prepare glass suspensions with a crystal drug in an amorphous carrier. The extrudates of F12, F13 and F14 were white to faintly yellowish strands. Since a single Tg and Tm were observed in DSC, and crystalline peaks of CBZ were confirmed in XRPD, it was determined that the extrudate consisted of crystalline drug in an amorphous carrier. The crystallinity of CBZ in the extrudates was 70% in F12, 80% in F13 and 61% in F14, suggesting that the majority of the CBZ existed in the crystalline state. In addition, the results of crystallinity analysis seemed reasonable because it has been shown that glass solutions of CBZ–SOL, CBZ– aPMMA and CBZ–COP could be prepared with drug loadings up to 40%, 20% and 33%, respectively.[25,26,32] The dissolution rates of extrudates were remarkably higher than those of pure CBZ and physical mixtures. Whereas F13 and the relevant glass solution (F3) showed a similar and rapid dissolution, the drug dissolution rates of F12 and F14 were lower than those of relevant glass solutions (F2 and F4). The cause of this difference is uncertain, but may be due to a difference in the dissolution rate of pure polymer, a difference in viscosity, or specific interactions between CBZ and aPMMA.

The Xplore extruder was qualified as a suitable screening tool for solid-dispersion formulations on a small scale. The first part of the investigation dealt with the OQ, and confirmed that the barrel temperature and the screw speed could be controlled precisely. Power consumption of the motor could also be monitored, and it was possible to calculate the SME. For the PQ, mixing capability and solid dispersion preparation were investigated. The dispersive mixing was a function of recirculation time and screw speed, and the degree of milling was related to the SME. The distributive mixing was completed in 1 min at 200 rpm regardless of the polymer type. It was found that higher SME values tend to be applied in comparison with those in large-scale extruders, which require sufficient cooling capacity. Eleven types of solid-dispersion systems were successfully prepared by altering the barrel temperature and the recirculation time, demonstrating the wide-range application capability of the small-scale extruder and the possibilities of HME itself.

Declarations Conflict of interest The Author(s) declare(s) that they have no conflicts of interest to disclose.

Amorphous precipitation The amorphous precipitation consists of amorphous drug clusters in a crystalline carrier. Although amorphous precipitation has been touched on in a number of review articles, there has been no actual case report involving DSC, XRPD and dissolution studies, possibly due to its extremely unstable nature. To overcome the stability issue to enable the solid-state characterization, we used NAP : aPMMA (F5) extrudate for the amorphous phase and MAN as the crystalline carrier. As a result, NAP : aPMMA : MAN (F15) was discharged from the die as a faintly yellowish opaque suspension and it immediately solidified as a faintly yellowish white mass. The extrudate showed a single Tg and Tm in DSC, and only MAN peaks were found in XRPD pattern, indicating the existence of amorphous clusters in the crystalline MAN. The in-vitro dissolution profile of the extrudate was very similar to that of F5, although the 12

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgements The Authors would like to thank BASF, Evonik and Pharmatrans Sanaq AG for the donation of the raw materials. The Authors also thank DSM Xplore for providing the opportunity to use the pharma micro extruder. The Authors thank Karin Matthée (Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Dusseldorf, Germany) for the DSC measurement. The Authors are grateful for the assistance of Elizabeth Ely (EIES, Lafayette, IN, USA) in preparing the manuscript.

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

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Small-scale HME

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© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

Investigation into mixing capability and solid dispersion preparation using the DSM Xplore Pharma Micro Extruder.

The goal of this investigation was to qualify the DSM Xplore Pharma Micro Extruder as a formulation screening tool for early-stage hot-melt extrusion...
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