RPS Pharmacy and Pharmacology Reports, 2024, 3, 1–8

https://doi.org/10.1093/rpsppr/rqad039
Advance access publication 24 November 2023
Research Paper

Twin-screw melt granulation for high-dose

paracetamol tablets
Steven A. Ross1,3, Md Sadeque Mithu1,3, Dennis Douroumis1,2,*
1
CIPER Centre for Innovation and Process Engineering Research, University of Greenwich, Chatham Maritime, Kent, UK
2
Delta Pharmaceutics Ltd., Chatham, Kent, UK
3
Custom Pharma Services, Brighton and Hove, Hove, UK

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Correspondence: Dennis Douroumis, Faculty of Engineering and Science, University of Greenwich, Kent, UK. Tel: +44(0)2083318440; E-mail: d.douroumis@gre.ac.uk
*

Abstract
Objectives In this study twin-screw melt granulation (TSMG) was used to produce sustained release formulations and improve the poor com-
pressibility of paracetamol (PMOL).
Methods By using various amounts of polyethylene glycol (PEG), a low melting point binder and ethyl cellulose (EC) as insoluble carrier, the
formation of high content of PMOL granules occurred at low processing temperatures (55°C).
Key findings X-ray diffraction and differential scanning calorimetry analysis showed the presence of partially crystalline PMOL in the extruded
granules. Compressed caplet tablets comprising of TSMG granules presented sustained release profiles for 3-4 h depending on the EC concen-
tration. The tablets showed excellent tabletability and low compaction forces were applied.
Conclusions TSMG can be used for the processing of drugs with poor compressibility actives for the compression of high-dose tablets.
Keywords: twin screw; melt granulation; high dose; paracetamol; tableting

Introduction Vaingakar et al. exploited the use of TSMG for the opti-
Wet granulation is a method of increasing particle size based misation of high drug-loaded tablets with sustained release
on the development of bigger aggregates of tiny initial powder of metformin HCl.[13] The process was optimised by using a
particles and is considered one of the fundamental and largely range of polyethylene glycol (PEG) with different molecular
adopted processes in pharmaceutical manufacturing.[1] Some of weights and hydroxypropyl cellulose as the carrier where
the major advantages of granulation processing are improved metformin doses were fixed at 50% w/w. In other studies,
content uniformity, homogeneity between the drug substance PMOL and sodium diclofenac sustained-released tablets
and excipients in the formulation, controlling the particle size with loadings varying from 40% to 80% were developed
distribution to prevent segregation, enhancing tablet ability of using Compritol ATO888 to provide dissolution rates up to
powder formulations and regulating the drug dissolution rates. 12 h.[14–16] The dissolution rates were controlled by adjusting
Twin-screw melt granulation (TSMG) is a promising con- the processing temperatures while stability through the addi-
tinuous granulation technique for the manufacturing of tion of inorganic excipients. However, the use of lipids entails
various dosage forms with better process control, reducing some pitfalls when lipids undergo crystallinity transformation
waste, easy to scale up, and a green technology that does not over time. Hence there is a need to identify drug carriers that
require the use of solvents.[2–4] Besides that, TSMG features provide sustained dissolution rates and excellent stability.
advantages over high-shear batch granulation, including a In this study, PMOL was used as a model drug, and ethyl
shorter residence time (usually under a minute in comparison cellulose (EC) as a hydrophobic polymer for the development
to a few minutes in batch operations), flexibility in process de- of sustained dissolution rates by means of TSMG. The ex-
sign, effective material mixing and reduced energy consump- cellent feasibility of EC, a polymer with thermoplastic prop-
tion. Gamlen and Eardley (1986) introduced for the first time erties, offers a range of controlled release profiles for highly
wet TSMG to produce paracetamol (PMOL) granules[5] fol- water-soluble drugs and it has been used as a matrix former in
lowed by Lindberg (1987) and later Kleinebudde (1998).[6, 7] extrusion.[17, 18] It has been reported in several studies that hot
Since that time, several studies made it evident that TSMG is a melt extrusion can be used as an appropriate technology to
suitable technology for the manufacturing of a wide range of develop mini-matrices using EC to sustain the release of ibu-
granular forms with enhanced dissolution rates,[8] improved profen.[19–21] However, TSMG allows the formation of PMOL
flowability[9] and compressibility.[10] TSMG has been inves- granules at lower processing temperatures with increased
tigated for the development of high-dose dosage forms of throughput. By altering the PEG levels, extruded granules
poorly compressible drugs such as acetaminophen.[11, 12] were obtained and subsequently compressed into tablets.

Received: April 22, 2023. Editorial Acceptance: November 23, 2023

© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
2 S.A. Ross et al.

Method time of 0.2 s per step;176 channels active on the PSD making
a total counting time of 35.2 s per step.
Materials
PMOL and EC were kindly donated from Mallinckrodt Particle size morphology and distribution
Chemical Ltd (Canada) and Colorcon (Dartford, UK), while SEM was used to examine the surface morphology of the
PEG (2000) was purchased from Sigma Aldrich (Gillingham, twin-screw extrudates. The samples were mounted on an alu-
UK), respectively. The solvent used in the HPLC analysis was minium stub using a double-sided adhesive carbon type and
HPLC grade and purchased from Fisher Chemicals (UK). All placed in a low-humidity chamber before analysis. Samples
the materials were used as received. were sputter coated with gold, and microscopy was performed
using a Cambridge Instruments Stereo-Scan S360 (UK), SEM
Twin-screw granulation
operating at an accelerating voltage of 20 kV.
Continuous twin-screw granulation experiments were car- The particle size distribution of the micronized extruded
ried out by using a Eurolab 16-mm twin-screw extruder granules of all formulations was measured by the Laser light
(ThermoFisher Scientific, Germany). The twin-screw extruder Scattering technique with a dry powder sample dispersion ac-
was equipped with a DD Flexwall®18 feeder (Brabender

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cessory (Scirocco 2000). During the laser diffraction measure-
Technology, Germany), which was set in its gravimetric ment, particles are passed through a focused laser beam. These
feeding mode. As shown in Table 1, physical mixtures of particles scatter light at an angle that is inversely proportional
PMOL, polymer and binder were blended before extrusion to their size. The angular intensity of the scattered light is then
in a Turbula mixer (100 rpm) (Basel, Switzerland) for 10 min. measured by a series of photosensitive detectors. The number
Two different extrudates were manufactured consisting of and positioning of these detectors in the Mastersizer 2000
fixed API, by combining the following components in dif- have been optimised to achieve maximum resolution across a
ferent concentrations: EC and PEG 2000 (Table 1). The barrel broad range of sizes.
temperature profile was set at 60°C temperature and screw
speed was maintained at 50 rpm for all batches (Table 2). Tablet compaction
Thermal analysis All excipients were passed through a mesh sieve with an aper-
ture of 500 µm before use. Tablet formulations (Table 3) were
The physical state of the pure drug and the extruded granules
blended in a TF2 turbula mixer (Basel, Switzerland) for 5 min.
were studied by differential scanning calorimetry (DSC) by
Blends were directly compressed in a Flexitab tablet press
using a Mettler–Toledo 823e (Greifensee, Switzerland) differ-
(Oyster-Manesty, Germany) using 22-mm caplet punches.
ential scanning calorimeter. Samples were accurately weighed
Dwell time was set at 30 min and the compaction force was
(2–3 mg) and placed in sealed aluminium pans. Measurements
varied from 10 to 20 kN to obtain the final caplets with a
were carried out in a nitrogen atmosphere. The flow rate of
hardness of 10–15 Kp.
dry nitrogen gas was 50 (mL/min). Samples were subjected to
run in two cycles of heating. First, the pans were heated with
a heating rate of 10.0°C/min from 0°C to 220°C in the first Hardness and friability tests
heating cycle. When the highest temperature was reached, just Caplet thickness and diameter were measured using Vernier
after 1 min, a cooling cycle was started with a cooling rate of callipers. The hardness was measured by Monsanto hardness
10.0°C/min from 220°C to 0°C. tester and a Roche friabilator was used for testing the fria-
bility of the caplets using the formula.
Powder X-ray diffraction % loss = 100 (Initial weight of the caplets – Final weight of
Powder X-ray diffraction (XRPD) was used to assess the caplets)/Initial weight of caplets
crystalline state of the pure substance in the extrudate formu-
lations. All formulations including pure PMOL, physical mix- In-vitro drug release study
tures and extruded granules were evaluated using Bruker D8 In vitro, drug release studies were carried out in 750 mL of
Advance in 2-theta mode, Cu anode at 40 Kv and 40 Ma, par- 0.1 M hydrochloric acid for 2 h using a Varian 705 DS dis-
allel beam Goebel mirror, 0.2 mm exit slit, LynxEYE position- solution paddle apparatus (Varian Inc., NC) at 100 rpm and
sensitive detector with 3° opening and LynxIris at 6.5 mm, 37°C ± 0.5°C. After 2 h of the dissolution process,150 mL of
sample rotation at 15 rpm. The samples were scanned from 2° 0.2 M solution of trisodium phosphate dodecahydrate was
to 40° 2-theta with a step size of 0.02° 2-theta and a counting added into each vessel to maintain the buffer at pH 6.8. At

Table 1 Composition of the granulated formulation

Formulation Drug Drug (%, w/w) Polymer Polymer (%w/w) Binder Binder (%)

F1 PMOL 60 EC 35 PEG 2000 5

F2 PMOL 60 EC 30 PEG 2000 10

Table 2 TSMG processing settings for the production of PMC/EC/PEG2000 granules

Feed rate (kg/h) Screw speed (rpm) T1 (°C) T2 (°C) T3 (°C) T4 (°C) T5 (°C) T6 (°C) T7 (°C) T8 (°C) T9 (°C)

0.25 50 30 30 60 160 60 60 60 30 30
Twin-screw melt granulation 3

predetermined time intervals, samples were withdrawn for narrow particle size distribution without fines suggesting that
HPLC assay. All dissolution studies were performed in dupli- no material remained ungranulated.
cate. The PMOL dissolution kinetics were determined using
the SigmaPlot 10.0 software (Systat Software Inc., Germany). Morphology
All formulations processed by TSMG were characterised by
HPLC analysis SEM to examine the surface morphology of the drug and
The release of PMOL was determined by using HPLC, Agilent extrudates. As shown in Figure 2, pure PMOL crystals exhib-
Technologies system 1200 series. A hychrome S50DS2-4889 ited mainly a rod-habit or prismatic microcrystal habit with
(5 μm × 150 mm × 4 mm) column was used for the HPLC anal- fine particulates on their surfaces. In other studies, it has been
ysis of PMOL. The wavelength was set at 276 nm. The mo- reported that PMOL crystals typically reveal an elongated
bile phase consisted of acetonitrile/water/phosphoric acid 1% habit.[22]
(50:50 v/v) and the flow rate was maintained at 1.5 mL/min
and the retention time was 4 min. A standard calibration X-ray powder diffraction
curve was prepared with concentrations varying from 10 to XRPD was used to investigate the crystalline state of PMOL.

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50 μg/mL with 20 μL injection volumes. The standard XRPD patterns of pure PMOL, physical mix-
tures of PMOL with EC and PEG, including granulates are
depicted in Figure 3, respectively. The bulk PMOL showed
Results and Discussion distinct peaks at 12.14°, 13.85°, 15.55°, 16.8°, 18.2°, 20.44°,
Operational parameters in granulation 23.51°, 24.4° and 26.60° 2θ values. The diffraction patterns
The objective of this study was 2-fold, to develop a high- of the physical mixture of different ratios of polymer and the
loading sustained-release formulation using TSMG and identical ratio of API presented the same crystalline peaks
process optimisation and to improve the tabletability of the to those of pure PMOL but with relatively lower intensities.
poorly compressible PMOL. For the screw configuration, The XRPD patterns of granulated formulations showed
three kneading zones (Figure 1) comprising 30°/60°/90° elem- characteristic peaks corresponding to bulk PMOL, which
ents for high-shear granulation. In addition, the low screw indicates the presence of crystalline PMOL in the granules
speed ensured longer residence time for binder melting and prepared by twin-screw granulation. It was also evident that
particle agglomeration. PMOL crystallinity remains the same even in crushed cap-
PMOL is known for its poor tabletability which becomes lets. However, the diffraction patterns of all granulates con-
more challenging for high drug dose formulations (>50%). firmed the presence of Form I of PMOL, and no new distinct
PEG 2000 was selected as the binder material due to its low crystalline peaks at different 2θ were observed. The XRPD
melting point, so the applied temperature profile wouldn’t ex- patterns of granulated formulations showed increased amor-
ceed 60°C and be less than the EC glass transition to avoid phous trends compared with the pure PMOL. Moreover, the
partial melting of PMOL during granulation. However, due peak intensities of the extruded formulations appear smaller
to PEG hydrophilicity, the binder amounts were kept be- than those of the respective physical mixtures with equal
tween 5% and 10% to avoid any effect on the PMOL dis- drug loadings suggesting different content of the amorphous
solution profiles. Furthermore, the selected binder amounts polymer.
(5%–10%) did not show any significant difference in the Windbergs et al. confirmed the presence of PEG affected
processing parameters such as feed rate and screw speed. the solid state of theophylline due to the drug–polymer
Torque indications remained stable at 50% of the Eurolab ­interactions, which led to changes in the drug’s crystalline
maximum settings. Finally, the designed processing settings state.[23, 24]
in both formulations (Table 1) produced large granules with
Thermal analysis
DSC was used to study the solid state of pure PMOL and
potential transformations under TSGM processing of the
Table 3 PMOL tablet formulations PMOL/EC/PEG formulations. As shown in Figure 4, the
melting endotherm of bulk PMOL was observed at 167.76°C
Excipients Amounts (%) while for PEG at 49.03°C. It has been previously reported
that PMOL presents three polymorphic forms such as stable
Extrudates 83.3 Form I (M.P 170°C), Form II which is highly unstable (m.p.
MCC 15.2 148°C), and the metastable Form (m.p. 160°C).[25] Based on
SiO2 0.5 the data obtained from DSC analysis, it can be seen that the
Magnesium stearate 1.0 polymorphic form of PMOL used in the current study is Form
I. The DSC scans of the PMOL/EC/PEG 5%, PMOL/EC/PEG
Total 100
10% granules showed melting endotherms at 168.58°C,

Figure 1 Screw configuration with three kneading zones for high-shear granulation.
4 S.A. Ross et al.

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Figure 2 SEM images of pure paracetamol (a and b) and PMOL/EC/PEG (60/35/5) granules. No crystals were observed on the granulated surface which
is also a sign of mixing during the granulation. The high-shear mixing generated during the extrusion process converted the crystalline shape of the
materials to granular shape which is also a sign of the increase of the amorphicity in the extrudate materials.

Figure 3 Diffractograms of pure paracetamol, physical and TSMG formulation.

167.31°C. It can be clearly seen a depression of the melting The same enthalpy depression could not be observed in the
enthalpy of bulk PMOL (626.97 mJ) due to the increase of thermograms of the physical mixtures. This is attributed to
the amorphous PMOL content in the granules. the high-shear mixing force during granulation which resulted in
Twin-screw melt granulation 5

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Figure 4 DSC thermograms of pure paracetamol, physical and granulated PMOL/EC/PEG (5, 10%) formulations.

the breakage of the intermolecular bond. Lakshman et al. stated fuse on the surface of the API due to the high shear.[26] The DSC
that polymers behave differently during TSMG processing and result complies with the XRPD analysis which also showed re-
convert to a rubbery state at elevated temperatures and eventually duced PMLO crystallinity in the granulated formulations.
6 S.A. Ross et al.

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Figure 5 Drug release profile of (a) PMOL/EC/PEG (60/35/5) and (b) PMOL/EC/PEG (60/35/10) at pH 1.2 to pH 6.8.

Table 4 Dissolution rate constants and determination coefficients of paracetamol would become efficient in maintaining the ther-
PMOL/EC/PEG (60/35/10) compressed tablets apeutic plasma level of paracetamol for a longer period, and
therefore, it will improve patient compliance.[28] The release
Dissolution models A B rate of paracetamol in dissolution media is highly likely de-
Zero order k° (% h−1) 21.10. ± 1.49 21.89. ± 1.45
pendent on the EC and the compaction force applied to pre-
R2 0.9617 0.9632 pare the tablet.
First order k1 (h−1) 0.459 ± 4.8 × 10−2 0.455 ± 4.8
It has been stated that in Percolation theory when a compo-
R2 0.9965 × 10−2 nent of the system undergoes a geometrical phase transition it
0.9497 starts connecting the whole system. Therefore, when a matrix
Higuchi kH (% h−1/2) 42.42 ± 2.5 42.57 ± 2.5 is composed of a water-soluble drug and a water-insoluble
R2 0.9233 0.955 polymer, drug release occurs by the dissolution of the active
Hixson– Crowell kHC (% h−1/3) 0.1282 ± 8.2 × 10−3 0.1305 × 10−3 ingredient through capillaries composed of interconnecting
R2 0.9760 ± 7.8 × 10−3 drug particle clusters and the pore network.[29–33] EC, a hy-
0.9786 drophobic polymer with thermoplastic properties, has been
Peppas kP (h−n) 0.392 ± 0.033 6.689 ± 0.076 widely used in several sustained-release dosage forms in-
R2 0.9830 0.9897 cluding granulation processing. As drug release continues, the
n 0.755 ± 0.059 0.776 ± 0.037 interconnecting clusters increase the pore network through
Baker & Lonsdale k (h−1) 0.044 ± 0.010 0.053 ± 0.010 which interior drug clusters can diffuse. The total number of
R2 0.853 ± 14.39 0.833 ± 15.65 EC particles increases when their particle size is reduced. In
that sustained-release matrix, drug diffusion occurs predomi-
nantly as the drug is leached from the dosage form via the po-
rous network formed when drug crystals are dissolved from
In-vitro dissolution studies the inert matrix.[34] The resulting pore network becomes less
Like other analgesics, PMOL has a short elimination half- extensive and more tortuous resulting in slower drug release.
life of about 2–3 h. As a result, it requires frequent drug ad- To control the burst release of paracetamol, the extruded
ministration to maintain therapeutic plasma level, and hence, formulation was compressed into caplets using a Flexitab press
paracetamol sustain release formulation would be the great with 22-mm caplet punches. Various studies were carried out
course of action.[27] A reduced dosage of sustained-release for the co-processing of lipid–polymer with Windbergs et al.
Twin-screw melt granulation 7

using trilaurin/PEG blends with various drugs to adjust the Funding

release profiles (e.g. increased rates).[23, 24]
This research received no specific grant from any funding
For better control of the dissolution rates a considerable
agency in the public, commercial, or not-for-profit sectors.
amount of microcrystalline cellulose (MCC; 15.42%), a hy-
drophobic polymer was added to the tablet formulation be-
fore caplet compression. Similarly, for our designed tablet Declaration of Interest
formulations, MCC was incorporated to avoid any burst re-
The author(s) declare that there are no conflicts of interest.
lease but also to improve the tablet compressibility. The final
tablet hardness varied from 10 to 15kP to investigate the ef-
fect of compression on the dissolution profiles. All batches Data Availability
demonstrated excellent tabletability as low compression
The data underlying this article will be shared on reasonable
forces (10–20 kN) were applied and friability of <0.1%.
request to the corresponding author.
Figure 5a and b illustrates the PMOL dissolution profiles at
different PEG and EC amounts. The release pattern was iden-

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tical for both formulations and provided sustained release References
for more than 3 h. Interestingly the compressed tablets of the 1. Dun J, Sun CC. Structures and properties of granules prepared by
TSMG formulations resulted in compact tablets and no burst high shear wet granulation. In: Handbook of Pharmaceutical Wet
release was observed However, it can be seen that for PMOL/ Granulation: Theory and Practice in a Quality by Design Paradigm.
EC/PEG 5% granules (Figure 5a), the release was extended United Kingdom: Elsevier Inc; 2018: 119–147.
to 4 h, while for the PMOL/EC/PEG 10%, full release was 2. Thompson MR. Twin screw granulation-review of current prog-
recorded after 3 h. The dissolution rates were not affected by ress. Drug Dev Ind Pharm 2015; 41: 1223–31. https://doi.org/10.3
the differences in the pH media as EC is non-ionic polymer. 109/03639045.2014.983931
However, from Figure 5, it is evident that the tablet hardness 3. Nandi U, Trivedi V, Ross SA et al. Advances in twin-screw granula-
tion processing. Pharmaceutics 2021; 13: 624.
did not affect the PMOL dissolution rates were almost iden-
4. Steiner, R., Jornitz, M. Continuous processing in the pharmaceu-
tical without any significant difference. This is attributed to
tical industry: status and perspective, Chapter 11. In: Continuous
the poor compressibility of PMOL and its hydrophilic nature. Manufacturing of Pharmaceuticals. NJ, USA: John Wiley & Sons
There are various mathematical models that can be em- Ltd; 2017, 369–403.
ployed to characterise medication dissolving rates based on 5. Gamlen MJ, Eardley C. Continuous extrusion using a Raker Per-
tablet features and to gain insights into the mechanism of kins MP50 (Multipurpose) extruder. Drug Dev Ind Pharm 1986;
drug release.[35–37] By using SigmaPlot software, the dissolu- 12: 1701–13. https://doi.org/10.3109/03639048609042604
tion mechanism for the PMOL/EC/PEG (60/35/10) tablet for- 6. Lindberg NO, Tufvesson C, Olbjer L. Extrusion of an efferves-
mulations at different compaction forces was investigated. As cent granulation with a twin screw extruder, Baker Perkins MPF
shown in Table 4, the Hixson–Crowell dissolution kinetics ap- 50 d. Drug Dev Ind Pharm 1987; 13: 1891–913. https://doi.
org/10.3109/03639048709068698
pear to be dominant for the PMOL tablets. This is when the re-
7. Kleinebudde P, Solvberg AJ, Lindner H. The power-consumption-
lease rates of the API are related to the dissolution velocity and
controlled extruder: a tool for pellet production. J Pharm Pharmacol
not the diffusion where the tablet dimensions decrease con- 1994; 46: 542–6. https://doi.org/10.1111/j.2042-7158.1994.tb03853.x
stantly by keeping their geometrical features. The determina- 8. Steffens KE, Wagner KG. Dissolution enhancement of carbamaz-
tion coefficients (R2) for the first order and the Hixson–Crowell epine using twin-screw melt granulation. Eur J Pharm Biopharm
mechanism are very similar and thus selection was based on 2020; 148: 77–87. https://doi.org/10.1016/j.ejpb.2020.01.006
the higher determination coefficient, smaller standard error of 9. Dhenge RM, Washino K, Cartwright JJ et al. Twin screw granu-
model parameters and smaller residual mean square.[35] lation using conveying screws: effects of viscosity of granulation
liquids and flow of powders. Powder Technol 2013; 238: 77–90.
https://doi.org/10.1016/j.powtec.2012.05.045
Conclusion 10. Batra A, Desai D, Serajuddin ATM. Investigating the use of poly-
meric binders in twin screw melt granulation process for improving
In conclusion, TSMG is a viable method for the development compactibility of drugs. J Pharm Sci 2017; 106: 140–50. https://
of sustained-release formulation of actives with poor com- doi.org/10.1016/j.xphs.2016.07.014
pressibility and at high doses. TSMG was feasible using low 11. Thakore SD, Reddy KV, Dantuluri AK et al. Application of twin-
amounts of a hydrophilic binder and PMOL was processed at screw melt granulation to overcome the poor tabletability of a high
low temperatures. The compressed tablets showed sustained dose drug. Pharm Res 2022; 39: 3241–57. https://doi.org/10.1007/
release profiles for 3–4 h without any premature release of s11095-022-03369-w
12. Vanhoorne V, Almey R, Beer TD et al. Delta-mannitol to enable
PMOL. The dissolution mechanism of the PMOL tablets ap-
continuous twin-screw granulation of a highly dosed, poorly
peared to follow the Hixson–Crowell mechanism.
compactable formulation. Int J Pharm Investig 2020; 583: 119374.
13. Vaingankar P, Amin P. Continuous melt granulation to develop high
drug loaded sustained release tablet of metformin HCl. Asian J Pharm
Author Contributions Sci 2017; 12: 37–50. https://doi.org/10.1016/j.ajps.2016.08.005
Conceptualisation: D.D.; methodology: D.D., S.A.R., M.S.M.; 14. Vithani K, Maniruzzaman M, Slipper IJ et al. Sustained release solid
formal analysis: D.D., S.A.R., M.S.M.; investigation: S.A.R., lipid matrices processed by hot-melt extrusion (HME). Colloids Surf
B 2013; 110: 403–10. https://doi.org/10.1016/j.colsurfb.2013.03.060
M.S.M.; resources: D.D; writing – original draft preparation:
15. Vithani K, Cuppok Y, Mostafa S et al. Diclofenac sodium sustained
D.D., S.A.R., M.S.M.; writing – review and editing: D.D., S.A.R.,
release hot melt extruded lipid matrices. Pharm Dev Technol 2014;
M.S.M.; visualisation: D.D.; supervision: D.D.; project admin- 19: 531–8. https://doi.org/10.3109/10837450.2013.805775
istration: D.D; funding acquisition: D.D.; All authors have read 16. Islam MT, Maniruzzaman M, Halsey SA et al. Development of
and agreed to the published version of the manuscript. sustained-release formulations processed by hot-melt extrusion by
8 S.A. Ross et al.

using a quality-by-design approach. Drug Deliv Transl Res 2014; dose randomized two period crossover comparison in healthy In-
4: 377–87. https://doi.org/10.1007/s13346-014-0197-8 dian adult volunteers. Int J Curr Pharm Res 2010; 2: 28–31.
17. Follonier N, Doelker E, Cole ET. Evaluation of hot-melt extrusion 28. Tan C, Graudins A. Comparative pharmacokinetic of Panadol
as a new technique for the production of polymer-based pellets for Extend and immediate release paracetamol in a simulated over-
sustained release capsules containing high loadings of freely sol- dose model. Emerg Med Australas 2006; 18: 398–403. https://doi.
uble drugs. Drug Dev Ind Pharm 1994; 20: 1323–39. https://doi. org/10.1111/j.1742-6723.2006.00873.x
org/10.3109/03639049409038373 29. Caraballo I, Leuenberger H. 2004. Critical points in hydrophilic
18. Follonier N, Doelker E, Cole ET. Various ways of modulating the matrices. Abstracts of the European Congress on Drug Delivery
release of diltiazem hydrochloride from hot-melt extruded sustained and Pharmaceutical Technology, Seville, May 10–12, 2004, 145.
release pellets prepared using polymeric materials. J Control Release 30. Miranda A, Millán M, Caraballo I. Study of the critical points in
1995; 36: 243–50. https://doi.org/10.1016/0168-3659(95)00041-6 the release and hydration kinetics of swellable matrix type con-
19. De Brabander C, Vervaet C, Remon JP. Development and evalua- trolled delivery systems. Int J Pharm 2006; 311: 75–81. https://doi.
tion of sustained release mini-matrices prepared via hot melt extru- org/10.1016/j.ijpharm.2005.12.012
sion. J Control Release 2003; 89: 235–47. https://doi.org/10.1016/ 31. Miranda A, Millán M, Caraballo I. Study of the critical points
s0168-3659(03)00075-0 in lobenzarit disodium hydrophilic matrices for controlled drug
20. Van Den Abeele WM, De Brabander C, Vervaet C, et al. Bioavaila- delivery. Chem Pharm Bull 2006; 54: 598–602. https://doi.

Downloaded from https://academic.oup.com/rpsppr/article/3/1/rqad039/7449586 by guest on 18 May 2024

bility of ibuprofen from hot-melt extruded mini-matrices. Br J Clin org/10.1248/cpb.54.598
Pharmacol 2004; 57: 366–7. 32. Miranda A, Millán M, Caraballo I. Investigation of the influence
21. De Brabander C, Vervaet C, Van Bortel L. Bioavailability of ibu- of particle size on the excipient percolation thresholds of HPMC
profen from hot-melt extruded mini-matrices. Int J Pharm 2004; hydrophilic matrix tablets. J Pharm Sci 2007; 96: 2746–56. https://
271: 77–84. doi.org/10.1002/jps.20912
22. Fairbrother JE. Acetaminophen. Anal Profiles Drug Subst 1974; 3: 33. Fuertes I, Miranda A, Millán M et al. Estimation of the perco-
1–109. lation thresholds in acyclovir hydrophilic matrix tablets. Eur J
23. Windbergs M, Strachan CJ, Kleinebudde P. Understanding the Pharm Biopharm 2006; 64: 336–42. https://doi.org/10.1016/j.
solid-state behaviour of triglyceride solid lipid extrudates and its ejpb.2006.05.009
influence on dissolution. Eur J Pharm Biopharm 2009; 71: 80–7. 34. Almedia A, Claeys B, Paul Remon J, Vervaet C. Hot melt extru-
https://doi.org/10.1016/j.ejpb.2008.05.015 sion developments in the pharmaceutical Industry. In: Douroumis
24. Windbergs M, Strachan CJ, Kleinebudde P. Influence on structural D (ed.), Hot-Melt Extrusion: Pharmaceutical Application. 1st edn.
variations on drug release from lipid/polyethylene glycol matrices. UK: John Wiley & Sons, Ltd, 2012, 43–69.
Eur J Pharm Biopharm 2009; 37: 555–62. 35. Costa P, Lobo JMS. Modelling and comparison of dissolution pro-
25. Joiris E, Martino PD, Berneron C. Compression behavior of ortho- files. Eur J Pharm Sci 2000; 13: 123–33.
rhombic paracetamol. Pharm Res 1998; 15: 1122–30. 36. Kitazawa S, Johno I, Mihouchi T et al. Interpretation of dissolu-
26. Jay PL, James K, Madhav V et al. Application of melt granulation tion rate data from in vitro testing of compressed tablets. J Pharm
technology to enhance tabletting properties of poorly compactible Pharmacol 1977; 29: 453–59.
high-dose drugs. J Pharm Sci 2011; 100: 1553–65. 37. Korsmeyer RW, Gurny R, Doelker E et al. Mechanism of solute
27. Shep D, Ojha A, Patel S et al. Bioequivalence and pharmacokinetic release from porous hydrophilic polymers. Int J Pharm 1983; 15:
evaluation of two formulations of paracetamol ER 650 mg: a single 25–35. https://doi.org/10.1016/0378-5173(83)90064-9