Journal of Drug Delivery Science and Technology 76 (2022) 103753

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Formulation development of curcumin-piperine solid dispersion via

hot-melt extrusion
Abdulmajeed A. Althobaiti a, Eman A. Ashour a, **, Mashan Almutairi a, b, Ahmed Almotairy a, c,
Mohammed Al Yahya a, d, Michael A. Repka a, e, *
a
Department of Pharmaceutics and Drug Delivery, University of Mississippi, School of Pharmacy, MS, 38677, USA
b
Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail, 81442, Saudi Arabia
c
Pharmaceutics and Pharmaceutical Technology Department, College of Pharmacy Taibah University, Al Madinah AlMunawarah, 30001, Saudi Arabia
d
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
e
Pii Center for Pharmaceutical Technology, The University of Mississippi, University, MS, 38677, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Curcumin is one of the major ingredients derived from turmeric (Curcuma Longa Linn). For many years, cur­
Drug release cumin was used in Indian traditional medicine to treat several diseases. It has anti-inflammatory, anti-cancer,
Curcumin and anti-diabetic activities. In addition, curcumin has a low aqueous solubility of 0.00575 mg/mL, which has
Piperine
been associated with its poor release profile. The aim of this study is to improve the release profile of curcumin
Amorphous solid dispersion
Hot-melt extrusion
utilizing the hot-melt extrusion technique (HME) to prepare curcumin-piperine solid dispersion (SD). Three
physical mixtures of curcumin, piperine, and Soluplus® were prepared with different ratios between the com­
positions. Two different extrusion temperatures (130 ◦ C and 140 ◦ C) were applied during the extrusion step.
Drug release studies for the pure compounds and the extrudates were performed using the USP apparatus II, and
the samples were analyzed using high-performance liquid chromatography (HPLC). Curcumin-piperine solid
dispersion was successfully prepared by hot-melt extrusion technology. Differential scanning calorimetry (DSC)
results showed the presence of endothermic peaks, one for curcumin at 179 ◦ C, and another for piperine at
132 ◦ C. However, these peaks were not observed in the extrudates thermograms, indicating the solubilization of
curcumin and piperine within the polymeric carrier at an amorphous state. The release studies revealed sig­
nificant improvement in curcumin release profiles for up to 9-folds in the formulations, compared to pure
curcumin.

1. Introduction refers to a combination of at least two different components, a hydro­

The bioavailability of oral drugs mainly depends on drug solubility,
absorption, metabolism, and elimination. Many drugs that are devel­
oped using advanced technologies such as computational modeling,
combinatorial chemistry, and high throughput screening have low bio­
availabilities [1]. Furthermore, 50% of the oral drugs are classified
under class II of the biopharmaceutical classification system (poorly
water-soluble) [2].
Solid dispersion (SD) is a well-known approach to address major
pharmaceutical challenges such as the low solubility and insufficient
physical or chemical stability of oral drugs. The term solid dispersion
phobic drug, and a hydrophilic carrier; the hydrophobic drug is
dispersed in the hydrophilic carrier at a solid state. With the increase in
numbers of poorly water-soluble drugs, the SD approach has been
vigorously investigated to overcome the limitations of many drugs [3].
Furthermore, several solid dispersion formulations have been approved
and marketed, as seen in Table 1. SD formulations are classified based on
the physical state of the carrier (crystalline or amorphous) and the way
that the drug is dispersed in the matrix [3]. Several techniques have
been used for formulating solid dispersion, including hot-melt extrusion
(HME), spray drying, melt fusion, and the supercritical fluid technique
[4].

* Corresponding author. Department of Pharmaceutics and Drug Delivery, University of Mississippi, School of Pharmacy, MS, 38677, USA.
** Corresponding author.
E-mail address: marepka@olemiss.edu (M.A. Repka).
URL: http://eashour@olemiss.edu (E.A. Ashour).

https://doi.org/10.1016/j.jddst.2022.103753
Received 16 June 2022; Received in revised form 24 August 2022; Accepted 26 August 2022
Available online 31 August 2022
1773-2247/© 2022 Elsevier B.V. All rights reserved.
A.A. Althobaiti et al.
Table 1
Examples of commercially solid dispersions.
Brand Name Manufacturer Drug
Gris-PEG Pedinol Pharmacal Inc. Griseofulvin
Kaletra Abbott Lopinavir, Ritonavir
Intelence Tibotec Etravirin
Certican Novartis Everolimus
Cesamet Valeant Pharmaceuticals Nabilone
In the 1980s, HME was first introduced in the pharmaceutical in­
dustry, and before that, it was used in food and plastic industries. HME
has been efficiently applied to address pharmaceutical challenges such
as poor solubility, insufficient stability, and unpalatable taste. More­
over, HME can provide additional advantages including continuous
processing, few processing steps, solvent free, and low cost [2]. HME has
three major processing steps, melting, mixing, and shaping. The mixture
of a carrier and an active pharmaceutical ingredient (API) passes
through three zones. First, the mixture is fed through the feeder and
transferred to the melting zone by the barrels. In the melting zone, the
mixture begins to soften, then moves to the mixing zone where the drug
is dispersed within the polymer. The shaping zone has the function of
reducing the pulsation flow and maintaining a uniform delivery rate
throughout the die (Fig. 1) [5]. Several dosage forms were successfully
developed utilizing HME including tablets, implants, granules, and
transdermal dosage form [6–9]. As any pharmaceutical technique, HME
comes with a few disadvantages, especially for heat-sensitive drugs [5].
The polyphenolic natural compound curcumin is the major extract
from turmeric (Curcuma Longa Linn) [10]. Curcumin has been heavily
investigated due to its safety and potential as an anti-cancer, anti-in­
flammatory, and anti-microbial compound [11]. The low solubility of
curcumin and its rapid metabolism by intestinal glucuronidation are
major factors that contribute to the low bioavailability. A dose of 2 g/kg
of curcumin was orally administrated to rats which resulted in a low
plasma concentration of 1.35 μg/mL after 1 h [12]. The same dose in
humans resulted in serum level of 0.006 μg/mL at 1 h [12]. In another
study, a single dose of radiolabeled curcumin was administered via an
intraperitoneal (IP) route, and a negligible amount of curcumin was
detected in the plasma (5 pmol/ml) [13,14]. Moreover, curcumin was
orally administered to 25 patients for three months with high risks of
uterine cervical intraepithelial, or neoplasmoral leucoplakia, the plasma
concentrations were assessed after 12 h and were 0.63 ± 0.06 μM, and
1.77 ± 1.87 μM, respectively [15]. Curcumin is metabolized by glu­
curonidation into dehydrocurcumin, tetrahydrocucumin, and hexahy­
drocurcumin [16]. Glucuronidation plays a major role in its metabolism
since 99% of curcumin is present in the plasma as a glucuronidation
conjugate [16]. Different dosage forms have been developed to enhance
the bioavailability of curcumin such as nanoparticles, liposomes, and
micelles [17–19].
Piperine is found in black pepper (Piper nigrum Linn) and has been
Fig. 1. A schematic for the hot-melt extrusion process.
2
Journal of Drug Delivery Science and Technology 76 (2022) 103753
widely used as an ingredient in food.20 Numerous studies have assessed
the pharmacology of piperine, which has anti-angiogenic, neuro­
protective, and chemopreventive activities [20,21]. Interestingly,
piperine has been reported to inhibit several metabolic enzymes, such as
Uridine 5- diphospho-glucuronosyltransferase (UGT), cytochrome P-450
enzymes (CYP3A4, CYP2E1, CYP1B2, and CYP1B1 isoforms), and sul­
fotransferases (SULT) [22].
The synergistic effects of the curcumin-piperine combination against
different diseases have been thoroughly investigated. An in vivo study
showed that the co-administration of curcumin with piperine signifi­
cantly alleviated diethylnitrosamine (DENA) induced hepatocellular
carcinoma [23]. The group treated with the combination had increased
the numbers of apoptotic cells compared to group treated with curcumin
alone [23]. Another study found that the combination of curcumin and
piperine inhibited Wnt signaling by 50% at 1 μL and full inhibition was
observed at 10 μL and reduced the breast cell self-renewal without
causing toxicity to differentiated cells [24].
Increases in plasma concentrations of vasicine, phenytoin, theoph­
ylline, norfloxacin, and ampicillin in humans and animals were observed
as consequences of piperine inhibition of cytochrome P-450 and UDP-
glucuronosyltransferase metabolic enzymes [25–28]. 2 g/kg of curcu­
min was administered alone or in combination with a dose of 20 mg/kg
of piperine to humans. Results showed that this combination improved
the plasma concentrations of curcumin in healthy volunteers; 0.18
μg/ml compared to 0.006 μg/ml for curcumin administered as the sole
agent [29]. Another pharmacokinetics study was carried out on rats,
which showed that piperine significantly improved the maximum serum
concentration (Cmax) of curcumin by 2.64-fold, and its area under the
curve (AUC0–24h) by 2.16-fold, compared to the administration of cur­
cumin alone [30]. The improvement in curcumin bioavailability was
correlated to the effect of piperine as a potent inhibitor for
UDP-glucuronosyltransferase (UGT) [30]. Based on this data and on the
fact that 99% of curcumin is present in plasma as a glucuronidation
conjugate, piperine was incorporated into the formulations to poten­
tially enhance the bioavailability of curcumin by acting as a UGT in­
hibitor [30].
The aim of this study is to improve the release profile of curcumin.
HME is used to prepare a solid dispersion of curcumin and piperine
utilizing the hydrophilic polymer Soluplus® (polyvinyl caprolactam-
polyvinyl acetate-polyethylene glycol). Important parameters such as
the effect of extrusion temperature, the loading capacity of the polymer,
Table 2
Composition of the three formulations.
Formulation Curcumin Piperine Soluplus®
F1 15% 5% 80%
F2 30% 10% 60%
F3 45% 15% 40%
A.A. Althobaiti et al.
Fig. 2. Physical appearance of the extrudates; (a) F1 at 130 ◦ C, (b) F1 at 140 ◦ C, (c) F2 at 130 ◦ C, (d) F2 at 140 ◦ C, (e) F3 at 130 ◦ C, and (f) F3 at 140 ◦ C.
and the interactions between the components were evaluated.
2. Materials and methods
2.1. Materials
Curcumin and piperine were purchased from Fisher Scientific (Fair
Lawn, NJ, USA) and Sigma-Aldrich (Milwaukee, WI, USA), respectively.
Soluplus® was obtained as a gift from BASF-SE (Ludwigshafen, Ger­
many). All other chemicals and solvents were of analytical grade and
were purchased from Fisher Scientific (Fair Lawn, NJ, USA).
3. Methods
3.1. Hot-melt extrusion
Three physical mixtures were prepared with different ratio between
the components (curcumin, piperine, and Soluplus®), as seen in Table 2.
The V-shell blender was used to blend the physical mixtures for 10 min
(Patterson-Kelley twin shell dry blender). The mixtures were then
extruded using the co-rotating twin-screw extruder (11 mm twin screw
extruder, Thermo Fisher Scientific) with a screw configuration consist­
ing of four conveying zones and three mixing zones. The extrusion step
was performed using two extrusion temperatures (130 ◦ C and 140 ◦ C),
with a feeding rate of 1 g/min, and a screw speed of 75 rpm. The same
extrusion parameters were used for all formulations.
3.2. Differential scanning calorimetry (DSC)
The physical states of the components before and after the extrusion
process were evaluated using differential scanning calorimetry (DSC)
(TA instruments DSC 25 Discovery series) with a heating rate of 10 ◦ C/
3
Journal of Drug Delivery Science and Technology 76 (2022) 103753
min ranging from 20 ◦ C to 200 ◦ C. The weights of the samples were
between 3 and 6 mg, and the weighed samples were placed in aluminum
pans. TRIOS software was used to analyze the thermograms of the
samples.
3.3. Thermalgravimetric analysis (TGA)
Thermalgravimetric analysis were performed for curcumin, piperine,
and Soluplus® to investigate their thermal stability using PerkinElmer
Pyris 1 TGA equipped with Pyris software (PerkinElmer Life and
Analytical Science, Shelton, CT, USA). The sample weight of the starting
materials (curcumin, piperine, and Soluplus®) was approximately 8–20
mg. The samples were heated from 30 ◦ C to 400 ◦ C with a heating rate of
18 ◦ C/min.
3.4. Scanning electron microscopy (SEM)
Surface morphologies of all extrudates were characterized using a
JSM-7200FLV Field-Emission Scanning Electron Microscope (JOEL,
Peabody, MA, USA) with an accelerating voltage of 5 kV and 10 kV with
a magnification of 50X to 500X. The samples were mounted on a carbon
pad, placed on an aluminum stub and sputter-coated with platinum
under an argon atmosphere using a fully automated Denton Desk V TSC
Sputter Coater (Denton Vacuum, Moorestown, NJ, USA) prior to
imaging.
3.5. Fourier transform infrared spectroscopy (FTIR)
Fourier transform infrared spectroscopy (Agilent Cary 630 with a
DTGS detector) was performed to study the interactions between the
components. The weighed samples (2–4 mg) were analyzed using a
scanning range from 1000 to 4000 cm− 1with a resolution of 1 cm− 1.
A.A. Althobaiti et al.
Fig. 3. Thermogram analysis: a) starting materials (curcumin, piperine, Sol­
uplus®), b) formulations F1 (130 ◦ C and 140 ◦ C), F2 (130 ◦ C and 140 ◦ C), and
F3 (130 ◦ C and 140 ◦ C).
Fig. 4. Thermogravimetric analysis of curcumin, piperine, and Soluplus®.
3.6. Drug content
Three weighted samples (25–40 mg) from each formulation were
dissolved in 20 mL of acetonitrile, followed by vortex stirring (Scientific
industries vortex genie-120 V) for 1 min. Standard calibration curves
4
Journal of Drug Delivery Science and Technology 76 (2022) 103753
were performed with r2 between 0.99 and 1. High performance liquid
chromatography (HPLC) consisting of a Waters 2695 separation Module
and Waters 2489 UV/Visible detector (Waters Technologies Corpora­
tion, Milford, USA) was used to analyze the samples. 0.1% orthophos­
phoric acid in a mixture of water and acetonitrile (50:50 v/v) was used
as the mobile phase. Chromatography was performed using the Phe­
nomenex C8 column (5 μm, 150 * 4.6 mm) and a flow rate of 0.8 mL/min
with a 10 μL injection volume, a column temperature of 35 ◦ C, and a
wavelength of 262 nm [31].
3.7. In-vitro drug release studies
The release study for pure curcumin, and piperine, and the formu­
lations F1, F2, and F3 which were extruded at 130 ◦ C and 140 ◦ C, were
conducted in a dissolution medium of 900 mL 0.1 N HCL (pH 1.2), with
0.1% sodium lauryl sulfate (SLS), and a paddle speed of 100 rpm, using
the USP apparatus II. The temperature of the medium was maintained at
37 ◦ C during the study. A sample volume of 2 ml was taken at pre­
determined time points (15, 30, 45, 60, 90, 120, 150, and 180 min), and
2 mL of fresh medium was added each time to maintain the volume at
900 mL. The samples were centrifuged for 10 min at 13,000 rpm, then
the supernatants were analyzed using the HPLC [31]. All dissolution
experiments were conducted in triplicates. Similarity factors were
calculated to compare the drug release profiles of the different
formulations.
3.8. Stability study
The study was conducted at a temperature of 25 ◦ C and 60% hu­
midity. Tests were performed at months 0 and 3. The extrudates were
packed in a glass vial and stored in the stability chamber. The purpose of
the study is to evaluate the integrity of the formulations during the
storage time, utilizing DSC, drug content, and drug release profile.
4. Results and discussion
4.1. Hot-melt extrusion
Initially, temperatures of 100 ◦ C, 110 ◦ C, and 120 ◦ C were used for
the extrusion, but the extrudates were trapped in the extruder. This in­
dicates that these temperatures were insufficient to solubilize the mix­
tures. The extrudates were successfully obtained using the following
parameters: the extrusion temperatures of 130 ◦ C and 140 ◦ C, a feeding
rate of 1 g/min, and a screw speed 75 rpm. The extrudates’ appearances
for formulations F1, and F2 were light red and brown-red color,
respectively. Whereas, F3 had a different appearance compared to the
other formulations, with a dark brown color (Fig. 2). This observation
can be explained by the fact that drug loading (45% curcumin and 15%
piperine) exceeded the polymer capacity and only small amounts of the
drugs were dissolved in the matrix.
4.2. Thermal analysis
The DSC results showed endothermic peaks (melting points) of cur­
cumin and piperine at 132 ◦ C and 180 ◦ C, respectively. The presence of
the melting points indicates that curcumin and piperine exist in crystal
states. Moreover, the glass transition temperature for Soluplus® was at
75 ◦ C. Endothermic peaks of curcumin and piperine were absent in all
formulations (F1, F2, and F3) at both extrusion temperatures (130 ◦ C,
140 ◦ C). This is due to the transformation of their physical states from
crystalline to amorphous (Fig. 3). The thermogravimetric analysis of the
raw materials showed approximately 10% decrease in their total mass at
temperatures 324 ◦ C for pure curcumin and at 333 ◦ C for both Soluplus®
and piperine (Fig. 4).
A.A. Althobaiti et al. Journal of Drug Delivery Science and Technology 76 (2022) 103753

Fig. 5. SEM images of; a) curcumin, b) piperine, c) Soluplus®, d)F1 at 130 ◦ C, e) F1 at 140 ◦ C, f) F2 at 130 ◦ C, g) F2 at 140 ◦ C, h) F3 at 130 ◦ C, and i) F3 at 140 ◦ C.

5
A.A. Althobaiti et al.
Fig. 6. FTIR analysis of the three formulations, (a) F1 with both extrusion
temperatures 130 ◦ C and 140 ◦ C. (b) F2 with both extrusion temperatures
130 ◦ C and 140 ◦ C. (c) F3 with both extrusion temperatures 130 ◦ C and 140 ◦ C.
6
Journal of Drug Delivery Science and Technology 76 (2022) 103753
Fig. 7. Drug content of curcumin and piperine of all formulations.
4.3. Scanning electron microscopy (SEM)
The SEM images revealed that F1 (5% piperine, 15% curcumin, and
80% Soluplus®), and F2 (10% piperine, 30% curcumin, and 60% Sol­
uplus®) had smooth surface areas without signs of crystals. This is
explained by the solubilization of the drugs within the matrix at an
amorphous state. Moreover, a crystal appearance was observed in F3,
which is due to the high drug loading (15% piperine, 45% curcumin,
40% Soluplus®), and may have exceeded the polymeric capacity. The
SEM images for F3 were inconsistent with DSC thermal analysis results,
which showed an absence of drug crystalline peaks in the extrudates.
The inconsistency could be related to the DSC limit of detection of
crystals, which is below 5% [32]. The presence of crystals in F3 can be
explained by the fact that the carrier Soluplus®, has a transition glass
temperature of 75 ◦ C, which is lower than the drugs’ melting points.
Consequently, the polymer will soften and solubilize the drugs before
reaching their melting points, preventing the appearance of crystalline
peaks (Fig. 5).
4.4. Fourier transforms infrared spectroscopy (FTIR)
The FTIR spectra for curcumin and Soluplus® showed carbonyl
group peaks at 1626 cm− 1. Moreover, the carbonyl peaks were broad­
ened in all formulations indicating the formation of the hydrogen bonds.
Furthermore, the disappearance of the hydroxyl peak at 3507 cm− 1 in
the spectrum of curcumin and the methylenedioxy peak at 2940 cm− 1 in
the spectrum of piperine support the formation of hydrogen bonds
(Fig. 6). The formation of hydrogen bonding with the carrier could have
impacts in enhancing the solubility and the stability of curcumin and
piperine.
4.5. Drug content
Three weighted samples (25–40 mg) from each formulation were
dissolved in 20 mL of acetonitrile, followed by vortex stirrer (Scientific
industries vortex genie-120 V) for 1 min. Results were processed
following HPLC analysis. Formulations F1 (130 ◦ C and 140 ◦ C), F2
(140 ◦ C), and F3 (130 ◦ C and 140 ◦ C) had a range of drug content of
85%–105% for both curcumin and piperine, as seen in Fig. 7.
4.6. In-vitro drug release studies
The release profile of pure curcumin had percentage of drug release
approximately 13% due to its low aqueous solubility. Furthermore,
formulations F1, F2, and F3 at both extrusion temperatures showed a
significant increase in curcumin release for up to 9-folds compared to the
A.A. Althobaiti et al.
Fig. 8. The release profiles for all formulations; (a) F1 at 130 ◦ C and 140 ◦ C, (c)
F2 at 130 ◦ C and 140 ◦ C, (c) F3 at 130 ◦ C and 140 ◦ C.
pure compound. Formulation F1 at both extrusion temperatures had a
percent drug release of 93%, which was the highest. This can be
explained by the high ratio of Soluplus® (80%) in the formulation.
Moreover, the percent drug release in F2 at both extrusion temperature
130 ◦ C and 140 ◦ C, were 86% and 77%, respectively. The increase of
drug loading in formulation F3 (45% curcumin and 15% piperine)
7
Journal of Drug Delivery Science and Technology 76 (2022) 103753
Fig. 9. Results of drug release studies to assess the stability of the formulations
at the third month; (a) F1 at 130 ◦ C and 140 ◦ C, (b) F2 at 130 ◦ C and 140 ◦ C, (c)
F3 at 130 ◦ C and 140 ◦ C.
affected the drug release profile, indicating that a portion of the drug is
still in the crystal form or is not completely dissolved within the carrier,
as seen in Fig. 8. A significant improvement in the release profile of
piperine was observed in formulation F1, in which it was 100% at
130 ◦ C, and 94% at 140 ◦ C, compared to pure piperine (75%).
A.A. Althobaiti et al.
Fig. 10. Thermogram analysis to assess the stability of the formulations at the
third month; F1 (130 ◦ C and 140 ◦ C), F2 (130 ◦ C and 140 ◦ C), and F3 (130 ◦ C
and 140 ◦ C).
Modifying the physical state and reducing the particle size of the
drug are advantages that can be achieved from using the solid dispersion
approach [33]. According to the Noyes-Whitney equation (equation
(1)), reduction in the particle size can improve drug wettability and
reduce particle agglomeration by increasing the surface area in contact
with the dissolution medium. Moreover, changing the physical state of
the drug to a high free energy state (an amorphous state) can minimize
the required energy to break the crystal lattice which might lead to a
rapid dissolution of the drug in the medium [33]. The release profiles of
curcumin and piperine in the formulations were improved due to the
increase in the surface area as a consequence of the particle size
reduction. Moreover, low energy was required to break the crystal lat­
tice for the optimized amorphous drug to release the drug during the
dissolution step.
dM/dt = AD (CS – Ct) / h (Equation 1)
Similarity factors were calculated to compare the drug release pro­
files between the formulations prepared with different extrusion tem­
peratures (equation (2)) [34]. The similarities in the dissolution profiles
had f2 values higher than 50, and closer to 100 for curcumin and
piperine. Extrusion temperatures 130 ◦ C and 140 ◦ C had no significant
impacts on the release profiles of the drugs.
∑
F2 = 50.log{[1+(1/n) (Rt-Tt)2]}− 0.5 (Equation 2)
Fig. 11. Percent drug content; a) curcumin and b) piperine during the stability study.
8
Journal of Drug Delivery Science and Technology 76 (2022) 103753
4.7. Stability studies
The purpose of the stability study is to evaluate the physicochemical
properties of the formulations throughout storage time. Results from the
release studies, drug content, and thermal analysis (DSC) showed no
significant differences between months 0 and 3, as seen in the drug
release study (Fig. 9), DSC analysis (Fig. 10), and drug content results
(Fig. 11). This indicates that all formulations remained physically and
chemically stable during this period, with no signs of degradation or
recrystallization. Furthermore, the increase in the formulation stability
is attributed to the molecular interaction between the components and
the ability of the carrier as a recrystallization inhibitor.
5. Conclusion
Curcumin and piperine formulations were successfully developed
utilizing the hot melt extrusion technique. Curcumin’s release profiles
were improved by up to 9-folds compared to the pure drugs. Soluplus®
was able to maintain the integrity of the formulations and prevent
recrystallization during the stability the three-months long stability
study. Moreover, using two different extrusion temperatures (130 ◦ C
and 140 ◦ C) had no significant impact on the physicochemical properties
of the formulations.
Authorship contribution
Abdulmajeed A. Althobaiti, Eman A. Ashour, Michael A. Repka
conceptualized the study. Abdulmajeed A. Althobaiti, Ahmed Almo­
tairy, Mashan Almutairi, and Mohammed Alyahya, investigated the
study. Writing-Original Draft: Abdulmajeed A. Althobaiti. Writing Re­
view and Editing: Eman A. Ashour and Michael A. Repka. Supervision
was provided by Michael A. Repka.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or conflicts of interest or personal relationships that could have
appeared to influence the work reported in this paper.
Data availability
Data will be made available on request.
A.A. Althobaiti et al.
Acknowledgement
This project was partially supported by Grant Number
P30GM122733-01A1, funded by the National Institute of General
Medical Sciences (NIGMS) a component of the National Institutes of
Health (NIH) as one of its Centers of Biomedical Research Excellence
(COBRE). Scanning Electron Microscopy images presented in this work
were generated at the Microscopy and Imaging Center by Dr. Vijaya­
sankar Raman, The University of Mississippi. This facility supported in
part by grant 1726880, National Science Foundation.
References
[1] E.H. Kerns, High throughput physicochemical profiling for drug discovery,
J. Pharmaceut. Sci. 90 (11) (2001) 1838–1858.
[2] H. Patil, R.V. Tiwari, M.A. Repka, Hot-melt extrusion: from theory to application in
pharmaceutical formulation, AAPS PharmSciTech 17 (1) (2016) 20–42.
[3] K. Dhirendra, S. Lewis, N. Udupa, K. Atin, Solid dispersions: a review, Pak. J.
Pharm. Sci. 22 (2) (2009).
[4] S. Janssens, G. Van den Mooter, Physical chemistry of solid dispersions, J. Pharm.
Pharmacol. 61 (12) (2009) 1571–1586.
[5] M.A. Repka, S.K. Battu, S.B. Upadhye, S. Thumma, M.M. Crowley, F. Zhang, et al.,
Pharmaceutical applications of hot-melt extrusion: Part II, Drug Dev. Ind. Pharm.
33 (10) (2007) 1043–1057.
[6] 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. 269 (2) (2004) 509–522.
[7] R. Bhardwaj, J. Blanchard, In vitro evaluation of poly (d, l-lactide-co-glycolide)
polymer-based implants containing the α-melanocyte stimulating hormone analog,
Melanotan-I, J. Contr. Release 45 (1) (1997) 49–55.
[8] N. Follonier, E. Doelker, E.T. Cole, Various ways of modulating the release of
diltiazem hydrochloride from hot melt extruded sustained release pellets prepared
using polymeric materials, J. Contr. Release 36 (3) (1995) 243–250.
[9] C. Aitken-Nichol, F. Zhang, J.W. McGinity, Hot melt extrusion of acrylic films,
Pharmaceut. Res. 13 (5) (1996) 804–808.
[10] V. Dhote, A. Upaganlawar, A. Ganeshpurkar, Traditional Indian therapeutic herbal
agent for the treatment of ischemic myocardial disorders: promises and
precautions. Herbal medicine: back to the future: volume 2, Vascular Health 2
(2019) 178.
[11] P. Anand, A.B. Kunnumakkara, R.A. Newman, B.B. Aggarwal, Bioavailability of
curcumin: problems and promises, Mol. Pharm. 4 (6) (2007) 807–818.
[12] N. Dhillon, B.B. Aggarwal, R.A. Newman, R.A. Wolff, A.B. Kunnumakkara, J.
L. Abbruzzese, et al., Phase II trial of curcumin in patients with advanced
pancreatic cancer, Clin. Cancer Res. 14 (14) (2008) 4491–4499.
[13] G. Shoba, D. Joy, T. Joseph, M. Majeed, R. Rajendran, P.S. Srinivas, Influence of
piperine on the pharmacokinetics of curcumin in animals and human volunteers,
Planta Med. 64 (4) (1998) 353–356.
[14] S. Perkins, R.D. Verschoyle, K. Hill, I. Parveen, M.D. Threadgill, R.A. Sharma, M.
L. Williams, W.P. Steward, A.J. Gescher, Chemopreventive efficacy and
pharmacokinetics of curcumin in the min/+ mouse, a model of familial
adenomatous polyposis, Cancer Epidemiol. Biomarkers Prev. 11 (6) (2002)
535–540.
[15] A.L. Chen, C.H. Hsu, J.K. Lin, M.M. Hsu, Y.F. Ho, T.S. She, J.Y. Ko, J.T. Lin, B.
R. Lin, M.S. Wu, et al., Phase I clinical trial of curcumin, a chemopreventive agent,
Journal of Drug Delivery Science and Technology 76 (2022) 103753
in patients with high-risk or pre-malignant lesions, Anticancer Res. 21 (2001),
e2900.
[16] M.H. Pan, T.M. Huang, J.K. Lin, Biotransformation of curcumin through reduction
and glucuronidation in mice, Drug Metab. Dispos. 27 (4) (1999) 486–494.
[17] C. Karikar, A. Maitra, S. Bisht, G. Feldmann, S. Soni, R. Ravi, Polymeric
nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for
human cancer therapy, J. Nanobiotechnol. 5 (2007) 3.
[18] W. Tiyaboonchai, W. Tungpradit, P. Plianbangchang, Formulation and
characterization of curcuminoids loaded solid lipid nanoparticles, Int. J. Pharm.
337 (1–2) (2007) 299–306.
[19] L. Li, F.S. Braiteh, R. Kurzrock, Liposome-encapsulated curcumin: in vitro and in
vivo effects on proliferation, apoptosis, signaling, and angiogenesis, Cancer 104 (6)
(2005) 1322–1331.
[20] M. Suhaj, Spice antioxidants isolation and their antiradical activity: a review,
J. Food Compos. Anal. 19 (6–7) (2006) 531–537.
[21] P. Chonpathompikunlert, J. Wattanathorn, S. Muchimapura, Piperine, the main
alkaloid of Thai black pepper, protects against neurodegeneration and cognitive
impairment in animal model of cognitive deficit like condition of Alzheimer’s
disease, Food Chem. Toxicol. 48 (3) (2010) 798–802.
[22] C. Atal, R. Dubey, J. Singh, Biochemical basis of enhanced drug bioavailability by
piperine: evidence that piperine is a potent inhibitor of drug metabolism,
J. Pharmacol. Exp. Therapeut. 232 (1) (1985) 258–262.
[23] Vikram Patial, et al., Synergistic effect of curcumin and piperine in suppression of
DENA-induced hepatocellular carcinoma in rats, 2, Environ. Toxicol. Pharmacol.
40 (2015) 445–452 ().
[24] M. Kakarala, D.E. Brenner, H. Korkaya, C. Cheng, K. Tazi, C. Ginestier, S. Liu,
G. Dontu, M.S. Wicha, Targeting Breast Stem Cells with the Cancer Preventive
Compounds Curcumin and Piperine, 2010.
[25] A. Allameh, M. Saxena, G. Biswas, H. Raj, J. Singh, N. Srivastava, Piperine, a plant
alkaloid of the piper species, enhances the bioavailability of aflatoxin B1 in rat
tissues, Cancer Lett. 61 (3) (1992) 195–199.
[26] G. Bano, V. Amla, R.K. Raina, U. Zutshi, C.L. Chopra, The effect of piperine on
pharmacokinetics of phenytoin in healthy volunteers, Plaza Med 53 (1987)
568–569.
[27] Breast Cancer Res. Treat. 122, 777–785. Bano G, Raina RK, Zutshi U, Bedi KL, Johri
RK and Sharma SC, Effect of pipe&e on bioavailability and pharmacokinetics of
propranolol and theophylline in healthy volunteers, Eur. J. Clin. Pharmaco.Z41
615–617 (1991).
[28] K. Janakiraman, R. Manavalan, Compatibility and stability studies of ampicillin
trihydrate and piperine mixture, 5, Int. J. Pharmaceut. Sci. Res. 2 (2011) 1176.
[29] G. Shoba, D. Joy, T. Joseph, M. Majeed, R. Rajendran, P.S. Srinivas, Influence of
piperine on the pharmacokinetics of curcumin in animals and human volunteers,
Planta Med. 64 (1998) 353–356.
[30] Ruoning Wang, et al., Involvement of metabolism-permeability in enhancing the
oral bioavailability of curcumin in excipient-free solid dispersions co-formed with
piperine, Int. J. Pharm. 561 (2019) 9–18 ().
[31] C. Moorthi, C.S. Kumar, S. Mohan, K. Krishnan, K. Kathiresan, Application of
validated RP–HPLC–PDA method for the simultaneous estimation of curcumin and
piperine in Eudragit E 100 nanoparticles, J. Pharm. Res. 7 (3) (2013) 224–229.
[32] Mark Saunders, et al., The potential of high-speed DSC (Hyper-DSC) for the
detection and quantification of small amounts of amorphous content in
predominantly crystalline samples, 1-2, Int. J. Pharm. 274 (2004) 35–40 ().
[33] A. Dokoumetzidis, P. Macheras, A century of dissolution research: from Noyes and
Whitney to the biopharmaceutics classification system, Int. J. Pharm. 321 (1–2)
(2006) 1–11.
[34] MDI, Drug DPID, Guidance for Industry, Center for Drug Evaluation and Research
(CDER), 1998, p. 1000.