European Journal of Pharmaceutical Sciences 102 (2017) 7184

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European Journal of Pharmaceutical Sciences

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

Dual-mechanism gastroretentive drug delivery system loaded with an

amorphous solid dispersion prepared by hot-melt extrusion
Anh Q. Vo a, Xin Feng a, Manjeet Pimparade a, Xinyou Ye a, Dong Wuk Kim a,
Scott T. Martin c, Michael A. Repka a,b,
a
Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
b
Pii Center for Pharmaceutical Technology, The University of Mississippi, University, MS 38677, USA
c
Material Chacterization, Thermo Fisher Scientic, Tewksbury, MA 01876, USA

a r t i c l e i n f o a b s t r a c t

Article history: In the present study, we aimed to prepare a gastroretentive drug delivery system that would be both highly re-
Received 18 October 2016 sistant to gastric emptying via multiple mechanisms and would also potentially induce in situ supersaturation.
Received in revised form 13 February 2017 The bioadhesive oating pellets, loaded with an amorphous solid dispersion, were prepared in a single step of
Accepted 27 February 2017
hot-melt extrusion technology. Hydroxypropyl cellulose (Klucel MF) and hypromellose (Benecel K15M)
Available online 28 February 2017
were used as matrix-forming polymers, and felodipine was used as the model drug. The foam pellets were fab-
Keywords:
ricated based on the expansion of CO2, which was generated from sodium bicarbonate during the melt-extrusion
Amorphous solid dispersion process. A 2n full factorial experimental design was utilized to investigate the effects of formulation compositions
Supersaturation to the pellet properties. The melt-extrusion process transformed the crystalline felodipine into an amorphous
Melt extrusion state that was dispersed and frozen in the polymer matrix. All formulations showed high porosity and were
Floating able to oat immediately, without lag time, on top of gastric uid, and maintained their buoyancy over 12 h.
Bioadhesion The pellet-specic oating force, which could be as high as 4800 N/g, increased signicantly during the rst
Gastroretentive drug delivery system hour, and was relatively stable until 9 h. The sodium bicarbonate percentage was found to be most signicantly
effect to the oating force. The ex vivo bioadhesion force of the pellets to porcine stomach mucosa was approxi-
mately 5 mN/pellet, which was more than ve times higher than the gravitation force of the pellet saturated with
water. Drug release was well controlled up to 12 h in the sink condition of 0.5% sodium lauryl sulphate in 0.1 N
HCl. The dissolution at 1, 3, 5, and 8 h were 512%, 2545%, 5580%, and 75% respectively for all 11 formulations.
In biorelevant dissolution medium, a supersaturated solution was formed, and the concentration was maintained
at around 2 g/mL, approximately 10-folds higher than that of the pure felodipine. All input factors signicantly
affected dissolution in the rst 3 h, but afterwards, only drug load and hypromellose (HPMC) content had signif-
icant effects. The prepared drug delivery system has great potential in overcoming low and uctuating bioavail-
ability of poorly soluble drugs.
Chemical: Felodipine (PubChem CID: 3333); hypromellose (PubChem CID: 57503849), hydroxypropyl cellulose
(PubChem CID: 71306830), sodium bicarbonate (PubChem CID: 516892); sodium carbonate (PubChem CID:
10340).
2017 Elsevier B.V. All rights reserved.

1. Introduction dissolution, low intestinal permeability, and narrow absorption win-

dow. Frequent problems of oral drugs include uctuating pharmacoki-
Owing to its many inherent advantages, oral administration is the netics, low bioavailability, and poor treatment efciency. Most of the
most preferable route of medicinal administrations, and thus has a encountered problems stem from the low solubility of APIs, as well as
prominent role in therapy. However, it is also known as an unpredict- the physiological uctuations.
able and uctuating treatment route, especially with regard to active It is estimated that approximately 40% of marketed APIs have prob-
pharmaceutical ingredients (APIs) that have poor solubility, slow lem with dissolution, and the majority of drug candidates currently in
development are poorly soluble, and their absorption sites limited to
the upper small intestine (Vasconcelos et al., 2007; Williams et al.,
Corresponding author at: Department of Pharmaceutics and Drug Delivery, Pii Center
for Pharmaceutical Technology, School of Pharmacy, The University of Mississippi,
2013). Therefore, ensuring that drugs are completely dissolved and
University, MS 38677, USA. ready for absorption before passing through the small intestine is very
E-mail address: marepka@olemiss.edu (M.A. Repka). crucial. To date, solid dispersion (SD) is one of the most successful

http://dx.doi.org/10.1016/j.ejps.2017.02.040
0928-0987/ 2017 Elsevier B.V. All rights reserved.
72 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184

strategies that enhances the dissolution and/or solubility of poorly solu- Hot-melt extrusion (HME) is widely known as a green processing
ble APIs. More advanced than conventional SD, amorphous SD can sig- technology in the SD development in which APIs are dispersed and sta-
nicantly enhance the apparent solubility (Taylor and Zhang, 2016), bilized in polymer and lipid matrixes (Repka et al., 2008); (Sarode et al.,
and therefore create a supersaturated solution in a non-sink condition. 2013). It is an excellent alternative to conventional techniques in the
This ultimately raises the in situ drug concentration at the absorption production of SDs (Repka et al., 2007). With the application of the pro-
site (Brouwers et al., 2009), and thus is potential to enhance the drug cess analytical technology, PAT strategy, it can be systematically scaled
absorption (Ueda et al., 2012), (Warren et al., 2010). up and developed as a continuous process (Tumuluri et al., 2008);
The gastrointestinal (GI) tract comprises many segments that are (Wahl et al., 2013); (Islam et al., 2015).
starkly different in both anatomy and internal environment, which cru- In our previous study (Vo et al., 2016), we focused on improving the
cially inuences the in vivo dissolution and absorption of drugs. Ideally, bioavailability of BCS class I drugs via a singular oating approach,
drugs are completely dissolved and absorbed before they reach the which is vulnerable to the dislodgement during the gastric emptying.
colon, as small intestine is the main absorptive region with surface To enhance applicability, in the present study, we developed a novel
area approximately 120 times higher than the total area of all other dual-mechanism gastroretentive DDS loaded with amorphous SD of a
parts of the GI tract (Rouge et al., 1996). However, the drugs' retention BCS class II drug by utilizing a single step of HME. The prepared DDS
time largely uctuates depending on meals, dosage forms, and inter- can potentially resist the gastric dislodgement via the synergistic effect
and intra-subjective variations (Newton, 2010); (Van Den Abeele et of oatation and bioadhesion. It also can generate and maintain in situ
al., 2016). The gastric retention time may vary from several minutes to drug supersaturation, a viable solution to the problem of poor
3 h in the fasted state and from 1 to 10 h in the fed state. Meanwhile, bioavailability.
the intestinal transition time, which is believed to be less variable, can
be as short as 1 h or as long as 7 h, or even longer (Weitschies et al., 2. Materials and Methods
2010). This ultimately results in large pharmacokinetic uctuations
and unpredictable treatment efcacy. Residing dosage forms in the 2.1. Materials
stomach is a potential approach overcoming these drawbacks.
A gastroretentive drug delivery system (DDS) can facilitate a more Felodipine (FEL) USP was purchased from Ria International LLC (East
predictable release and allow for more complete absorption. Because Hanover, NJ, USA). Sodium bicarbonate (SBC) USP/NF was purchased
in vivo dissolution is limited in the stomach, drug release tends to be from Spectrum Chemical Mfg. Corp. (Gardena, CA, USA). HPMC K15M
more controlled (Taupitz et al., 2013). Furthermore, drug concentration (Benecel K15M) and HPC (Klucel MF) were kindly provided by Ashland,
surrounding the dosage forms is maintained low, since the dissolved Inc. (Lexington, KY, USA). HPLC solvents and all other reagents used in
drug is continuously transported away from them, downward the intes- the study were of analytical grade and were purchased from Fisher Sci-
tine. This is very important with regard to low solubility drugs, as a entic (Pittsburgh, PA, USA).
pseudo-sink condition is created and in situ recrystallization is
prevented. In addition, drugs gradually enter the absorption site as
free molecules ready for absorption which is practically meaningful to 2.2. Extrusion Processing
drugs with narrow absorption window and unpredictable bioavailabili-
ty (Streubel et al., 2006). Finally, such a formulation maximizes the ab- Initially, raw materials were separately passed through a USP #35
sorption area as the whole GI tract surface for all drug molecules. Since mesh sieve to remove aggregates and clumps. A mixture of 100 g of
the drugs always release at the rst segment, they all have the potential each formulation was prepared and physically mixed until a homoge-
to be absorbed at any point throughout the tract. In contrast, for conven- nous physical mixture was obtained.
tional DDSs, absorption area decreases signicantly along with their The system used for preparing the foamed strands was comprised a
downward movement. Therefore, taken as a whole, the gastroretentive twin screw extruder (Process 11, Thermo Fisher Scientic, Odessa, TX,
amorphous SD is a viable solution to the pharmacologic problems of USA) equipped with a 1.5 mm circular die insert, a chiller, a feeder, and a
narrow absorption window, low solubility, and poor absorbability. conveyor belt that was adjusted to synchronize with the main module.
The short gastric retention time of conventional dosage forms might A modied screw conguration (Fig. 1) was used for the experiment.
limit the advantages of controlled-release DDSs, which usually prolong The temperature of all eight zones on the barrel and the die was set at
drug release up to 12 h or longer. It is estimated that the average drug 165 C. Screw speed and feeding rate was set at a constant 200 rpm
retention time in the stomach is around 30 min (Newton, 2010), and and 5 g/min, respectively.
in the small intestine it is around 3 h (Podczeck, 2010). This indicates The system was allowed to heat-soak for 10 min to establish thermal
that conventional controlled-release dosage forms might pass through equilibrium prior to processing. The rst 30 g of the extrudate was
the small intestine, the main absorption site, in 1/4 to 1/3 of their discarded to ensure that the samples were collected when the extruder
lifespans, resulting in incomplete drug absorption. Therefore, they was operating at a steady state. To get a uniformly cylindrical extrudate,
might only be suitable for APIs that can be absorbed well in the colon. the conveyor speed was adjusted to synchronize with the extrudate for-
Otherwise, the gastroretentive DDS is a viable approach to the con- mation rate. The straight extrudates were subsequently cut into 2.0-mm
trolled release drugs. long pellets and stored in tight glass bottles at 2025 C.
There are numerous approaches to the fabrication of a
gastroretentive dosage form, including oating DDSs, sinking DDSs, 2.3. Differential Scanning Calorimetry
expanding DDSs, bioadhering DDS, and magnetic DDSs (Lopes et al.,
2016). Among those, oating and bioadhesive DDSs are the most exten- Differential Scanning Calorimetry (DSC) was used to investigate the
sively researched as well as developed as marketed products (Pawar et thermal behaviour of the materials and formulations, as well as to con-
al., 2012). However, the oating DDS can be dislodged by the gastric rm the compatibility of the API and the excipients. The pure compo-
emptying in an average of every 2 h (Singh and Kim, 2000), while the nents, their binary mixtures (1:1), physical mixtures, and formulations
bioadhesive DDS can be detached from the stomach wall by the were subjected to DSC experimentation (Diamond DSC Perkin Elmer,
mucus turnover that frequently renews the gastric mucosa outer layer Waltham, MA, USA). Samples weighing 25 mg (for pure compounds)
(Chen et al., 2010). The combination of the oating and bioadhesive ap- or 812 mg (for physical mixtures) were loaded onto a crimped alumin-
proaches, however, could potentially result in a synergistic effect that ium pan (non-hermetic pan) and placed in the DSC system. The samples
could effectively resist the stomach's physiological activities to maintain were then stabilized by holding at a temperature of 45 C for 2 min and
gastric retention for a suitable period of time. followed by heating from 45 C to 200 C at a ramp rate of 10 C/min
 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184 73

Fig. 1. Modied screw conguration used to prepare the foamed pellets loaded with amorphous solid dispersion.

under an inert nitrogen ow of 20 mL/min. The thermograms were Japan) with a copper tube anode and a standard sample holder. The
analysed to detect for thermal events. diffractograms were collected at room temperature (2025 C) with
the following parameters: step width of 0.02/s, scanning range from
2.4. Experimental Design 5 to 40 on a 2 scale; generator tension (voltage) 40 kV; generator cur-
rent 100 mA; scanning speed 10/min.
A two-level full factorial design was applied to address the effects of
formulation compositions on pellet characteristics. By using this model, 2.7. Densities and Porosity
signicant input factors and interactions between factors can be identi-
ed. Furthermore, the effects of input factors can be mathematically de- To measure geometric density, uniform straight strands were cut
scribed and outcomes can be predicted for each set value of input into 10-cm cylinders with at surfaces on both sides. The diameter
factors. The results of the regression are very useful for designing oper- (d), an average of 5 different measurements along the length of the cyl-
ation spaces in the quality by design (QBD) approach. inder, and length (h) of the cylinders were measured using digital calli-
The regression equation is expressed as follows: pers (d = 0.01 mm, VWR Digital Calliper, Radnor, PA, USA). The
cylinders were weighed (m) using a high precision balance (Analytical
Y i bi ai1 X 1 ai2 X 2 ai3 X 3 ai12 X 1 X 2 ai13 X 1 X 3 ai23 X 2 X 3 Balance XSE 204, Mettler Toledo, Switzerland). The pellet geometric
density was calculated using the following equation:
where Yi is the response number i, bi is the constant, and ai1, ai2, ai3, ai12,
ai13, ai23 are the coefcients of the encoded factors. The signicance of 4m
Dgeometric 2
the model and effect of factors determined the regression and one- hd
way analysis of variance (ANOVA) performed on Modde 8.0 software
(Umetrics Inc., Sweden). Three independent variables were investigat- The pellet true density was determined using a gas pycnometer
ed: Drug load, HPMC content, and SCB percentage. The output variables (AccuPyc II 1340, Micrimeritics, Norcross, GA, USA) using helium gas.
were drug release proles, porosity, and oating strengths. The measurements were replicated ve times and the data were proc-
essed using the built-in software suite. The results reected the density
2.5. Scanning Electron Microscopy of the matrix skeleton, as the helium gas occupied the entirety of the
vacuous space within the matrix. The porosity of the oating pellets
The pellets were carefully cut to produce at surfaces for SEM exam- was calculated using the following equation:
ination. The samples were stuck on aluminium stubs held with a dou-
ble-sided carbon adhesive lm and placed in the coating chamber. The V void Dgeometric
P 1
coating was performed in an inert gas environment prepared by remov- V geometric Dskeletal
ing the air at 40 mm Hg, then lling the chamber with high purity nitro-
gen. The samples were then coated with gold by using a Hummer 6.2 where Vvoid is the total volume of the air pockets inside the pellets, and
Sputtering System (Anatech LTD., Battlecreek, MI, USA) in nitrogen en- Vgeometric is the volume of the pellet as a whole object. Dgeometric and
vironment at 120 mm Hg and current of 18 mA. The coating was tripli- Dskeletal are the geometric density and true density of the pellets,
cated for 45 s each. The pellets' surface topography was examined using respectively.
a scanning electron microscope (SEM) operating at an accelerating volt-
age of 5 kV and a magnication of 45 (JEOL JSM-5600; JEOL, Inc., Pea- 2.8. Sample Process for Quantitative Analysis
body, MA, USA).
Using a mortar and pestle, the extrudate was ground into a ne pow-
2.6. X-Ray Diffraction der. It was then accurately weighed to an amount equivalent to 10 mg of
FEL and transferred into a 100-mL volumetric ask along with 40 mL
The X-Ray diffraction experiments were performed by using a acetonitrile and 20 mL methanol. The ask was sonicated for 5 min
Rigaku X-ray equipment (D/MAX-2500PC, Rigaku Corporation, Tokyo, (Branson 2510, Branson Ultrasonic Corp., Danbury, CT, USA) before
74 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184

adding 30 mL phosphate buffer (pH = 3) and continuously shaken for 2.12. Ex Vivo Bioadhesion Force Measurement
15 min using a mechanical shaker. The buffer was added to the volume
and mixed well. A volume of 5 mL was centrifuged at the relative centri- Fresh porcine stomachs were taken from the slaughterhouse, proc-
fuge force of 16,000 g for 10 min at 25 C (Centrifuge 5415R, Eppendorf essed, and used within 1 day. The stomachs were opened and gently
AG, Eppendorf, Germany). The supernatant was diluted ve times with rinsed with 0.9% NaCl solution. They were then mounted onto a at sur-
the mobile phase and ltered with a 0.45-m membrane before loading face, and the outer muscle layer was removed using a surgical knife. The
into the autosampler of the high-performance liquid chromatography remaining portion with the mucosa was then cut into suitably sized
(HPLC) system. pieces and kept in 0.9% NaCl solution before experimentation.
The bioadhesion force was measured using a Texture Analyzer Sta-
2.9. HPLC Analysis ble Micro Systems (TA-TXi2, Texture Technologies Corp. UK) equipped
with Exponent V 6.1.5.0 data processing software. One portion of stom-
Felodipine was analysed using a Waters 600 HPLC system (Waters ach mucosa was xed rmly onto the instrument basement and another
Corp., Milford, MA, USA) equipped with an autosampler, UV/VIS detec- was mounted tightly onto the probe (3 3 cm, at surface). The pellets
tor, and a Phenomenex Luna C18 column (5 m, 250 mm 4.6 mm). were placed in FaSSGF at 37 C for at least 5 min before testing. Twenty
The HPLC program was developed after referencing the USP Felodipine saturated pellets were placed evenly onto the mucosa surface, which
extended release tablet monograph. The mobile phase was a mixture of was xed onto the instrument basement. Both mucosa on the basement
acetonitrile: methanol: phosphate buffer (6.9 g mono basic sodium and the probe were moistened with FaSSGF prior to experimentation.
phosphate in a 1000 mL solution, adjusted with phosphoric acid to Operation parameters were set as following: pretest and test speed of
pH 3) at a ratio of 3:2:1 (v/v). The elution was performed at a ow the probe were 1 mm/s, trigger force was 0.05 N, applied force was
rate of 1.0 mL/min in an isocratic mode. The injection volume was set 0.1 N, and contact time was 120 s. The adhesion force was determined
at 10 L for the assay samples, and 50 L for the dissolution samples. as the peak on generated force-time plots. The experiment was con-
The signal was detected at a wavelength of 362 nm. Two linear calibra- ducted ve times for each formulation.
tion curves were established, one ranging from 0.4375 g/mL to 28 g/
mL (R2 = 0.9998), which was used to analyse the assay samples and 3. Result and Discussion
dissolution in sink condition samples. The other ranged from
0.0252 g/mL to 3.220 g/mL (R2 = 0.9983), which was used to quantify In the present study, we rst aimed to fabricate a hydrophilic matrix
the dissolution in fasted state simulated gastric uid (FaSSGF) samples. because the model drug was a poorly soluble compound, and we
hypothesised that such a matrix would help enhance drug dissolution.
HPMC is the most important hydrophilic polymer in the formulation
2.10. In Vitro Drug Release of controlled-release DDSs. It can swell to form an erodible hydrogel
that controls drug release from the matrix (Siepmann and Peppas,
Floating pellets (10 mg FEL) were subjected to dissolution testing in 2001). In addition, HPMC is an excellent carrier for amorphous drugs
a sink condition and biorelevant dissolution medium. The sink condition owing to its high Tg (N180 C) and ability to maintain the supersatura-
dissolution medium consisted of 900 mL 1% SLS in 0.1 N HCl solution. tion of drugs in aqueous media (Konno et al., 2008); (Yang et al., 2015).
The un-sink dissolution media was the FaSSGF whose composition However, it is not a good candidate for HME because HME generates
was described by Marques et al. (2011) and Jantratid et al. (2008). The high pressure, high torque, and requires a high processing temperature
paddle method and USP dissolution apparatus type 2 (Hanson SR8; that is close to HPMC's degradation temperature. Thus, HPC was chosen
Hanson Research, Chatsworth, CA, USA) were used with a setting tem- as the secondary polymer to enable the HME process because it has a
perature of 37 0.5 C and paddle rotation speed of 100 rpm. At chemical structure very similar to that of HPMC; thus, it is potentially
predetermined time points, a volume of 2.0 mL dissolution media was able to be melt-miscible with HPMC. Furthermore, its low Tg can be
withdrawn and 2.0 mL fresh dissolution media was added. The samples used to modulate the Tg of the polymer blend according to the Gor-
were subsequently ltered through 0.2 m, 13 mm PTFE membrane l- don-Taylor equation (Forster et al., 2001).
ters (Whatman, Inc., Haverhill, MA, USA). Samples of the dissolution The foamed strands were formed as the extrudate exited the die
test in biorelevant media were diluted with an equal volume of an ace- based on the expansion of CO2 generated from thermal degradation of
tonitrile: methanol (2:1) mixture before injection into the HPLC system. NaHCO3. We hypothesised that the processing temperature would be
A volume of 10 L (assay test) or 50 L (dissolution test) was injected higher than the degradation temperature of the foaming agent, but si-
into the HPLC system for analysis by the above method. multaneously low enough to ensure the stability of formulations during
processing. The optimum processing temperature was chosen based on
2.11. Floating Strength Determination the DSC experimental results as shown in Fig. 2. The degradation pro-
cess reached its peak at approximately 150 C and nished below
The pellet oating force was determined via resultant-weight, which 170 C. Therefore, the processing temperature was chosen to be
was measured based on the lever principle. The apparatus, operation, 165 C, the lowest temperature where the foaming effect of SBC could
and calculation were described previously (Vo et al., 2016). The ve- be maximized. This temperature was also higher than the melting tem-
point calibration curve was established by measuring the resultant perature of the API, facilitating API dispersion into the polymer matrix.
weight of known counterpoise weights. Using a USP dissolution appara- A series of preliminary experimentations were conducted to deter-
tus II (Hanson SR8), 1000 mg of the pellets were placed in 900 mL mine the parameters for experimental feasibility. The screw congura-
FaSSGF at 37 0.5 C and continuously stirred at 50 rpm. At tion was redesigned as shown in the Fig. 1 to enhance the
predetermined time points, the vessel was removed from the dissolu- performance of the foamed extrusion process. A small reverse mixing
tion system and was carefully placed on a vessel holder. The vessel hold- zone was set at the second barrel zone to create a temporary melting
er was then slowly lifted to collect all oating pellets under a perforated seal to prevent gas leakage. In addition, all three mixing zones were
cone. A basement was used to support the holder and keep the system moved forward towards the barrel end, and the rst two mixing zones
steady. The resultant weight was read as the value on the balance. were simplied to enable the materials to be conveyed into the tight
After measuring, the vessel was placed back into the dissolution system, area more quickly. To compensate the rst two small mixing zones,
with stirring, until the next measurement. The oating strength was cal- the last mixing zone was increased in size and designed more complexly
culated by plugging resultant weight values into the regression equa- to ensure a good homogeneity effect. The feeding rate was xed at
tion of the calibration curve. 5 g/min and screw speed was set at 200 rpm to satisfy various
 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184 75

Fig. 2. Thermogram of API, foamed agent, selective formulations, and selective physical mixtures in which sodium bicarbonate was substituted by sodium carbonate (drug load in physical
mixture 2 was 6%; and Phys. Mix. 7 was 14%).

requirements, such as the ability to ll the barrel, to synchronize with lower Tg. In addition, it is possible that the melted FEL plasticized and/or
the strand conveyance, and to generate a suitable foamed strand. produced a lubricant effect that further decreased the torque. The total
The design of experiment (DOE) was used to elucidate the effects of retention time of the formulations in the barrel and die was approxi-
formulations on the properties of the pellets. The HPMC content, drug mately 80 s.
load, and SBC percentage were chosen as independent factors with
their variable ranges shown in Table 1. HPC was considered a compen- 3.1. Micromeritics Properties
sated variable. From the preliminary study, the variation range of HPMC
content ranged from 25% to 35%. If it was higher than 40% the torque Eleven DOE formulations (Table 2) were fabricated and character-
would increase and the extrudate would be too hard that did not ized. The SEM images of the pellets' cross-sectional surfaces revealed
allow for the formation of foamed strands (Fig. 3B); if it was lower vacant spaces inside the pellets created by the expanded CO2 in all 11
than 25%, the extrudate was too soft, and the strands would burst and formulations. The size and distribution of vacant spaces depended on
ultimately shrink, such that the foam structure could not be maintained the HPMC content and SBC percentage. Generally, the SBC percentage
(Fig. 3A). The SBC range of 59% was chosen such that a suitable foamed had a covariant effect on the size and degree of vacant spaces, and
structure could be obtained. If the SBC was out of the range, either the HPMC content had a contravariant effect, as shown in Fig. 3.
pellets would have too low porosity to enable them oat, or they The micromeritics properties of the pellets are presented in Table 3.
would be too porous to be effective. The drug load varied around 10%, The density of all 11 formulations was lower than 1 g/cm3, allowing
based on the presumption that the drug and polymers would be them to immediately oat on top of the gastric uid (Fig. 4), additionally
completely miscible and physically stable. conrming their foamed structure. The extrudate drug load ranged from
All 11 DOE formulations were successfully prepared. Within the ex- 97.70100.16% compared to theoretical values, which implies that the
perimental ranges, the system worked smoothly and uniformly foamed drug was stable during processing. The loss on drying (105 C for
strands were obtained. When a steady state was established, the torque 15 min) of the samples was considerably low (1.181.86%) compared
and die pressure remained relatively stable around 2.5 Nm (25%) and 26 to their respective physical mixtures. Under the high processing tem-
bars, respectively. Even though the operation temperature was lower perature, most of water evaporated once the extrudate exited the die.
than the Tg of HPMC, the torque was quite low because HPMC was mis- Since water would largely effect on molecular mobility via decreasing
cible with the softened HPC and was able to form a polymer blend with the Tg of SD, low water content would signicantly increase the physical
stability of an amorphous SD.
Because the pellet true density (or skeletal density) of all 11 formu-
Table 1
Experimental independent factors and their variation. lations was almost the same, the pellet porosity was proportional relat-
ed to the pellet geometry density. Hence, the porosity proportionally
Independent variable Symbol Unit Coded value Real value
reected the initial oatability of the pellets, which could not be mea-
Upper Lower Upper Lower sured because of large uctuations. The regression result conrmed
HPMC content X1 % +1 1 35 25 that the model used was suitable for describing the relationship of the
Drug load X2 % +1 1 14 6 input factors to pellet porosity (R2 = 0.984, Q2 = 0.746). While drug
SBC percentage X3 % +1 1 9 5 load did not signicantly affect pellet porosity, both the HPMC content
HPMC: Hypromellose; SBC: Sodium bicarbonate. and SBC percentage had signicant effects (P b 0.01). The SBC
76 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184

Fig. 3. Representative scanning electron microscope (SEM) images of the pellets' cross-sectional surface. (A) 0% HPMC; (B) 50% HPMC; (C) 25% HPMC and 5% SBC-N1; (D) 35% HPMC and
5% SBC-N2; (E) 25% HPMC and 9% SBC-N7; (F) 35% HPMC and 9% SBC-N8.

percentage positively affected pellet porosity, as it controlled the oating kinetics with no lag time, with oating time N 12 h and oating
amount of temporary blowing agent generated. In contrast, HPMC con- force as high as 5000 N/g.
tent inversely affected pellet porosity. It moderated the softening of the
hot polymer matrix, and thus matrix expansion. Its high Tg also helped 3.2. Thermal Properties
to preserve the foamed structure by quickly hardening the extrudate
when it exited the die. However, the SBC percentage effect was three The thermal behaviour of materials and formulations were elucidat-
times higher than that of HPMC content. ed using DSC. From the results shown in Fig. 2, no thermal event was de-
Previously, there were a few published studies on oating dosage tected in the range of 40190 C on the thermogram for HPC and HPMC
forms prepared using HME. Those studies focused on highly soluble that could conrm the amorphous nature of these two polymers. An
compounds, used Eudragit RS as a matrix forming polymer, and owed exothermic peak at 146 C corresponded to the melting peak of the crys-
high risk of dislodgement by gastric emptying. In one study, oating talline FEL raw material. On the thermogram for SBC, a large, broad
tablets were prepared based on the expansion of CO2 generated from
the reaction of SBC and acetohydroxamic acid (Fukuda et al., 2006);
however, the continuous reaction of the residual acid and base during Table 3
Micromeritic properties of the foamed pellets (SD).
storage is problematic for stability. Recently, gas-generated oating par-
ticulates, whose buoyancy depended on gastric pH, were prepared Form. Geometric True Porosity Physical Pellet Drug
using HME (Malode et al., 2015). However, this process is possibly un- density density (%) mixture LOD LOD load
(g/cm3)a (g/cm3)b (%) (%) (%)a
practical for product development because of extremely low through-
put and long resident time inside the barrel (9 min). In comparison to N1 0.9136 1.2945 29.18 4.49 1.71 6.03
the other oating dosage forms, the particulate buoyancy was limited 0.0174 0.0005 0.08
N2 0.9758 1.2884 24.36 4.78 1.86 6.05
because the lag time (N3 min); after 5.5 h and 10.5 h, N 50% and 90% 0.0214 0.0001 0.02
of the particulates sank, respectively. More recently, oating foamed N3 0.9165 1.2883 28.95 4.15 1.57 14.29
pellets were prepared by injecting an inert foaming agent into the ex- 0.0121 0.0007 0.21
truder barrel (Vo et al., 2016). The obtained pellets showed good N4 0.9537 1.2864 26.07 4.44 1.51 14.38
0.0197 0.0000 0.19
N5 0.7656 1.2924 40.66 4.35 1.48 6.20
0.0189 0.0004 0.02
Table 2 N6 0.8402 1.2932 34.87 4.61 1.43 6.16
Experimental formulation compositions. 0.0181 0.0001 0.11
N7 0.7878 1.2871 38.93 3.97 1.22 14.55
Formulation Run order X1 X2 X3 HPC (%)
0.0193 0.0006 0.19
N1 11 25 6 5 64 N8 0.8328 1.2943 35.44 4.27 1.18 14.46
N2 8 35 6 5 54 0.0254 0.0002 0.14
N3 9 25 14 5 56 N9 0.8708 1.2886 32.50 4.39 1.37 10.09
N4 4 35 14 5 46 0.0181 0.0006 0.13
N5 10 25 6 9 60 N10 0.8726 1.2935 32.35 4.37 1.43 10.03
N6 3 35 6 9 50 0.0057 0.0002 0.04
N7 6 25 14 9 52 N11 0.8805 1.2878 31.74 4.39 1.38 10.22
N8 7 35 14 9 42 0.0135 0.0006 0.07
N9 5 30 10 7 53
LOD: Loss on drying.
N10 2 30 10 7 53 a
n = 3.
N11 1 30 10 7 53 b
n = 5.
 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184 77

Fig. 4. Appearance of the pellets in dissolution medium. (A) Initial. (B) 1 h. (C) 4 h. (D) 8 h. (E) 12 h. (F) Formation of the gel layer after 1 h.

exothermal event that noticeably started at 110 C could be interpreted in the diffractogram of formulations with both low and high drug load
as a thermal degradation peak. CO2 and H2O generated from the SBC (Fig. 5).
degradation reaction could evaporate and remove heat from the DSC During the extrusion process, melted FEL was expected to disperse
sample, thus causing the heat to ow to the sample to compensate for at the molecular level into the softened polymer matrix. In the experi-
the heat lost, resulting in the exothermic peak. There was no detectable mental concentration range, the formulations were presumed to be ei-
thermal event in the thermograms of all 11 formulations. This further ther in a solution region (thermodynamic stable) or in a spinodal
suggests that the crystalline FEL was transformed into an amorphous region (metastable) on the API-polymer phase diagram, thus maintain-
form, and the SBC in the starting formulations had maximized its effect. ing the API amorphous state. Moreover, the combination of HPMC and
The amorphous form of FEL in the formulations was conrmed by XRD HPC formed a polymer blend whose Tg (calculated using the Gordon-
results. The sharp peaks in the region of 23o to 26o that presented in Taylor equation) was remarkably higher than the storage temperature;
pure FEL and the low drug load physical mixture could not be detected thus, the drug molecules were able to be frozen into the polymer matrix.

Fig. 5. XRD diffractogram of crystal FEL, polymers, low drug load physical mixture, and selective formulations with low and high drug load.
78 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184

To investigate the physical stability of the formulations, the samples Table 4

were packed tightly into light-protected glass vials and stored at 40 C Floating efciency of the pellets.

for 6 months. At this elevated storage temperature, we hypothesised Form. Floating strength (N/g)
that the mobility of molecules would increase and accelerate the recrys- 1h 9h
tallization process; therefore, this method could be utilized to detect
Average SD Average SD
early physical instability. There was no thermal event detected on the
thermograms of all 11 formulations tested for stability, conrming F1 1287 360 1334 376
F2 2348 406 1880 298
that the amorphous state of FEL was maintained. The experimental
F3 1619 325 1486 214
data support the hypothesis of a relatively stable amorphous SD. F4 2881 476 2287 305
F5 3484 478 3093 416
3.3. Floating Kinetics F6 4072 594 3491 404
F7 3864 345 3086 464
F8 4523 290 4148 284
A oating dosage form might experience many obstacles that pre- F9 3093 327 2719 319
vent it from maintaining buoyancy for a sufcient period of time. Float- F10 3109 510 2756 194
ing force is the most crucial parameter in evaluating buoyancy, as it F11 3186 261 2545 358
shows how well a dosage form can oat (Timmermans and Moes,
1990). High oating force enables the dosage form to resist submer-
gence and assists it in reoating when the submergence might tempo- factors, SBC percentage had the greatest effect on both probability and
rarily occur. capability (Fig. 7). This effect on pellet oatability probably acted via
Owing to their low density (d b 1.00), all 11 formulations could oat two different mechanisms; on the one hand, it controls pellet porosity
immediately on top of FaSSGF. Upon contact with the gastric uid, the (Table 5), which is proportionally related to the initial oating force
polymers rapidly absorbed water and swelled, with a gel layer forming and the pellet's intrinsic oating ability. On the other hand, SC in the pel-
to cover the matrix, trapped bubbles, and maintain oatation for over lets would react with acid in the gastric uid and generate CO2, increas-
12 h (Fig. 4). To investigate the oating kinetics, the buoyant force of ing the oating force. This would explain why the oating force
the pellets in FaSSGF was measured at different time points over 12 h. remained relatively stable up to 9 h. As for the role of HPMC, its high vis-
The oating kinetics greatly varied from one formulation to the other cosity contributed to gel layer density, retarded polymer dissolution,
(Fig. 6). The initial oating force could not be measured accurately, as and thus trapped air bubbles in the matrix more effectively. The greater
the simultaneous effects of the swelling process and the reaction of so- the HPMC content, the higher the oating force observed. FEL, a hydro-
dium carbonate (SC), which was formed from the thermal degradation phobic compound, inuenced pellet oatability via its contribution to
of SBC and remained in the formulations, with acid from the environ- the hydrophobicity of the matrix, retarding water penetration into pel-
ment caused the force to continually increase. The increase in the oat- lets and positively affecting the oating force. Drug load contributed the
ing force in the rst 60 min was proportionally related to the SBC least to the pellet buoyancy. With regard to the oating force during the
percentage. Afterwards, it became relatively constant up to 9 h, before rst hour, there was no potential interaction (P N 0.58) between input
dropping off. During the rst 9 h, the bubbles escaping from the matrix factors, so the regression could be considered a linear regression. How-
were compensated by the CO2 generated from SC, ultimately keeping ever, there was a potential interaction between HPMC content and drug
the oating force stable (Table 4). When the SC was exhausted, the load at 9 h (P = 0.056), which inferred a possibly signicant effect of
loss of vacant space in the matrix overcame gas generation, that (drug load HPMC content) to oating force.
would make the oating force decrease at a rapid rate.
The regression results of the oating force at 1 h and 9 h (Table 5) 3.4. Bioadhesive Properties
conrmed that the model used could accurately describe the effects of
input factors on output variables (P b 0.05, R2 N 0.98, Upon contact with gastric uid, the pellets would absorb water and
Q2 N 0.485 0.50). The oating force was signicantly (P b 0.05) swell to produce a highly viscous and sticky hydrogel outer layer. The
governed by all three factors in a positive manner. Among the three high viscosity enabled the pellets to initially adhere to the stomach

Fig. 6. Specic oating kinetics of the pellets (SD, n = 3).

 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184 79

Table 5 gastric emptying process, which occurs periodically as a physiological

Floating efciency regression result. activity of the stomach.
Variables Pellet porosity Floating force at 1 h Floating force at 9 h The stomach adhesion potential of the pellets was determined by
Coefcient P Coefcient P Coefcient P
measuring the bioadhesion force. All 11 formulations were subjected
to ex vivo bioadhesion force measurement. The bioadhesion force of a
Model 0.002 0.001 0.001
single measurement varied from 3.056.98 mN/pellet which was over
Constant 0.3227 0.000 3042.2 0.000 2620.3 0.000
X1 0.0170 0.006 373.0 0.004 306.5 0.002 three times larger than gravity of a saturated pellet, which ultimately
X2 0.0030 0.395 224.9 0.022 158.1 0.018 weighed b100 mg even at its heaviest. This could be inferred that
X3 0.0462 0.000 876.5 0.000 760.9 0.000 every pellet could adhere well onto the stomach wall to prevent from
X1 X2 0.0039 0.244 28.1 0.637 97.5 0.056 being dislodged with gastric uid during gastric emptying stage.
X1 X3 0.0056 0.121 26.1 0.660 1.87 0.961
X2 X3 0.0016 0.610 32.8 0.583 18.0 0.648
The average bioadhesion force per pellets was in the range of 4.42
R2 = 0.984 R2 = 0.984 R2 = 0.991 1.53 mN to 5.67 1.08 mN (Fig. 8). The differences in bioadhesion force
Q2 = 0.746 Q2 = 0.485 Q2 = 0.555 of the 11 formulations were not signicant (P = 0.875, one-way ANOVA
R2, goodness of t; Q2, goodness of prediction. test using SPSS 22). There was no signicant difference in the force be-
tween any two formulations (P N 0.926, Tukey test using SPSS 22). This
might be explained by the fact that the chemical structure of HPMC and
wall. In addition, the HPC and HPMC polymer chains might penetrate HPC, the two components that generate the adhesion force, are very
into the mucus layer and interlock with the glycoproteins of the mucosa similar. Therefore, the hydrogen bond intensity was not signicantly af-
(Varum et al., 2010). Furthermore, upon contact with the stomach mu- fected by the HPMC/HPC ratio in the experimental range.
cosa, hydrogen bonding between\\OR (R = hydrogen or a short chain More interestingly, the average bioadhesion force was found to be
hydrocarbon) groups of the polymer and\\NH2 and\\COOH groups of relatively stable over the experimental time in the FaSSGF. This can be
the mucosa protein occur (Andrews et al., 2009), further increasing the explained by the following: initially, when the outer polymer layer is
bioadhesion force of the pellets. Because both HPMC and HPC are rich in not completely saturated, the hydrogel layer is highly viscous and
\\OR groups, the generated hydrogen bonds signicantly contribute to dense, allowing the pellets to adhere more strongly to the stomach mu-
the bioadhesion force. The total adhesion force was thus expected to be cosa, but the size of the matrix is relatively small, so the contact area of a
high enough to keep the pellets attached to the stomach wall during the pellet to the mucosa is also small. Later on, the pellets are more

Fig. 7. Representative contours describing the effect of the variables on the oating strength of the pellets at (A) 1 h and (B) 9 h.
80 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184

Fig. 8. Average bioadhesion force per pellet of the experimental formulations (SD, n = 5).

saturated, and the gel layer became less adherent, but the matrix size is biological activities, and is likely to remain in the stomach for a sufcient
increased, so the contact area of the matrix to the mucosa is increased, period of time.
thus maintaining the adhesion force. The matrix then proceeds into a
steady state, in which the balance between the dissolution of polymer 3.5. Drug Release Kinetics
molecules at the matrix surface and the gelling of polymer molecules
in the inner core is established, and the matrix size and the gel structure 3.5.1. In the Sink Condition
are stable enough to keep the adhesion force constant. The steady state In the sink condition (SLS 1% in HCL 0.1 N, pH 1.2), drug release could
was maintained up to 9 h before the polymer-dissolving process be controlled up to 12 h. Even though dissolution was largely different
exceeded the polymer-gelling process, making the gel layer less adher- between formulations, the pattern of the drug release proles was
ent and decreasing the adhesion force. very similar (Fig. 9) because the release mechanism was similar.
The combination of oating and bioadhesion has the potential to HPMC and HPC rapidly swelled once the pellets contacted the gastric
generate a synergistic effect that increases the probability of gastric re- uid, forming an outer gel layer (Fig. 4F). Drug molecules then diffused
tention. During the gastric emptying stage (phase 4 of the gastric phys- through the gel layer out to the dissolution medium. Knowing this, the
iology cycle), the contents of the stomach are pushed forward to the thickness, denseness, and hydrophilicity of the gel layer would control
intestine along with gastric uid; the pellets are expected to stay adher- the drug release kinetics. As can be seen from the results of the dissolu-
ing to the stomach wall, thus ensuring that the pellets would not be tion regression, drug load, SBC percentage, and HPMC content all affect-
pushed out and would remain in the stomach. However, if the pellets ed drug release differently over the time.
did detach from stomach wall because of the mucus shedding process, The average dissolution at 1, 3, 4, and 8 h (Table 6) was used to cor-
their buoyancy will keep them in the stomach. A new cycle of mucosal relate the independent factors with dependent variables. From the re-
adhesion would start with a new mucosal layer. Therefore, this gression results (Table 7), the three factors of drug load, SBC
bioadhesive oating DDS has high potential resistance to gastric percentage, and HPMC content signicantly affected drug dissolution

Fig. 9. Dissolution proles of experimental formulations in the sink condition (SD, n = 3).
 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184 81

Table 6 popular approach to perform dissolution tests limited to quality control

Drug release kinetics. purposes. Such the tests are usually conducted to conrm reproducibil-
Form. Drug release (%) ity between production batches, which are manufactured with the same
1h 3h 5h 8h
formulation and technology. However, such a high concentration of sur-
factants in dissolution medium would not occur in a biological environ-
Average SD Average SD Average SD Average SD
ment. Therefore, the correlation between in vitro dissolution and in vivo
N1 11.3 1.0 42.8 4.3 75.7 5.6 97.7 4.4 dissolution is very limited. In contrast, a dissolution test in biorelevant
N2 5.6 0.6 28.3 3.2 65.1 4.1 83.0 3.4
medium would provide more relevant information on the biological
N3 5.4 1.0 27.7 1.4 67.2 6.0 89.2 4.8
N4 4.9 0.4 26.5 2.6 58.7 2.3 79.1 3.6
conditions of interest and the in vivo behaviour of dosage forms.
N5 10.9 1.1 44.4 2.1 79.7 4.5 101.3 4.9 The dissolution proles of 11 formulations and crude API in FaSSGF
N6 6.0 0.5 30.3 5.9 62.0 2.6 83.9 6.9 were shown in the Fig. 11. The dissolution proles of all formulations
N7 7.6 1.3 36.4 1.3 72.4 3.2 92.6 2.6 were signicantly different from that of the pure drug at all time points
N8 9.2 2.4 34.8 1.6 61.0 4.2 80.7 5.4
(P = 0.000, one-way ANOVA test). From 4 h onward, the drug concen-
N9 8.7 1.4 31.5 3.6 67.4 3.9 90.8 3.7
N10 8.6 0.5 32.4 3.1 67.9 4.3 91.2 4.9 tration reached maximum values, which were not signicantly different
N11 7.9 1.5 31.4 4.7 68.2 3.8 92.4 5.5 between all 11 formulations (P N 0.05, one-way ANOVA test). Drug re-
lease was slow during the rst hour but increased from 1 to 4 h, before
drug concentration peaked at approximately 2 g/mL; this could be con-
at 1 h and 3 h (P b 0.03). The signicance of the (HPMC content Drug sidered the drug's apparent solubility. From that time onward, the drug
load) and (SCB percentage Drug load) variables (P b 0.05) at 1 h indi- concentration was maintained relatively stable at its apparent solubility.
cate that there were interactions between these factors, meaning that In comparison, drug dissolution from the crude API was very slow, and
the effect of one factor was dependent on the values of the others. On its maximum concentration was 10 folds lower than that of the
the prediction contour plots, the interactions between factors showed formulations.
non-straight curves (Fig. 10). Later on, at 5 h and 8 h, SBC lost its signif- Initially, because the polymer had not completely swelled the drug
icance (P N 0.098) and no potential interaction between the factors was was held in the dense matrix. Water absorption was greater than diffu-
observed. Drug release was signicantly inuenced by HPMC content sion outow, thus impeding drug release from the matrix. After the rst
and drug load (P b 0.03). stage, the gel layer became less dense, and the balance of water absorp-
HPMC moderated the drug release prole by controlling the proper- tion in and diffusion out was established in a manner that drug release
ties of the gel layer covering the matrix. The HPMC content was covari- increased. This explains why drug release increased from 1 to 5 h, when
ant with the thickness and denseness of the gel layer, but contra-variant the drug concentration steadily increased to its limit, the apparent solu-
with drug diffusion. The negative effects of HPMC content were de- bility. Dissolution then transitioned into a steady state where the bal-
scribed quantitatively by the regression equation. FEL showed a nega- ance between drug release from the matrix and the drug nucleation/
tive effect on drug dissolution, similar to HPMC, but its presence was crystallization was established such that the drug concentration
mostly related to the hydrophilicity of the matrix. An increase in drug remained relatively stable at the apparent solubility. An advantage of
load rendered the matrix more hydrophobic, and thus decreased the amorphous drugs compared to their counterparts is that a supersatura-
water absorption rate and drug release (Fig. 10). Unlike HPMC and tion state can be obtained. The increase in the solubility is dependent on
FEL, which retarded drug release from the matrix, SBC facilitated drug the difference in free energy between the amorphous and crystalline
release. It inuenced the drug release prole via its effects on pellet po- form (Murdande et al., 2010). Once dispersed in the polymer matrix,
rosity and matrix hydrophilicity. As SBC percentage was covariant with an amorphous SD can further enhance apparent solubility compared
the pellet porosity, it promoted water absorption into the matrix and to pure amorphous APIs (Jackson et al., 2016), since free drug molecules
created channels for drug release. In addition, SC formed from SBC dur- directly enter the dissolution media along with polymer molecules,
ing the extrusion process is highly soluble, attracting water and making which would retard the nucleation process. The presence of polymers
the matrix more hydrophilic. These effects would result in an increase in generated a parachute effect that would help maintain the supersatura-
drug release. However, over the time, the swelled polymers would ll tion state (Xie and Taylor, 2016).
out matrix channels, and SBC would totally dissolve and diffuse out of The regression results of various output variables can be utilized to
the matrix, rendering it insignicant. design spaces for QBD. On the basis of the predetermined qualities of a
nished product and the requirement range of various response vari-
3.5.2. In Biorelevant Dissolution Medium ables, the properties of the nished product can be set. On a contour
Normally, to create a sink condition for dissolution testing of poorly graph of each response variable, a satisfactory region where the re-
soluble drugs, a high concentration of surfactants (much higher than sponse variable meets constraints can be determined. By overlaying all
their CMC) will be added to dissolution medium. It is a simple and contours, an overlapping space will be generated by all the individual

Table 7
Dissolution statistical analysis and coefcients of regression.

Variables % Drug release 1 h % Drug release 3 h % Drug release 5 h % Drug release 8 h

Coefcient P Coefcient P Coefcient P Coefcient P

Model 0.010 0.006 0.002 0.012

Constant 7.816 0.000 33.306 0.000 67.746 0.000 89.251 0.000
X1 1.008 0.011 3.598 0.003 5.527 0.000 6.088 0.001
X2 0.790 0.024 2.173 0.016 2.382 0.006 2.583 0.026
X3 0.738 0.030 2.309 0.013 0.943 0.098 1.049 0.234
X1 X2 1.171 0.004 2.545 0.006 0.943 0.074 0.945 0.232
X1 X3 0.216 0.339 0.202 0.695 0.519 0.256 0.608 0.416
X2 X3 0.661 0.029 1.331 0.051 0.325 0.454 0.297 0.681
R2 = 0.958 R2 = 0.967 R2 = 0.980 R2 = 0.954
Q2 = 0.664 Q2 = 0.586 Q2 = 0.722 Q2 = 0.623

R2, goodness of t; Q2, goodness of prediction.

82 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184

Fig. 10. Regression plots illustrating the effect of the formulation compositions on the drug release kinetics at (A) 1 h, (B) 3 h, (C) 5 h, and (D) 8 h.

contour plots, called a sweet spot region. The sweet spot region can to ensure that formula compositions do not fall out of the sweet spot
be considered a space in which processing parameters can vary without area.
any change in product qualities. It can be considered equivalent to the
design space concept of QBD, which is dened as ranges within which 4. Conclusion
parameters can vary without considering as a change in process (Yu,
2008). For example, if the expected quality of the pellets were: 8% b Dis- Bioadhesive oating pellets loaded with amorphous SD were suc-
solution 1 h b 12%, 30% b Dissolution 3 h b 45%, 45% b Dissolution cessfully fabricated using HME technology. The results of this study
5 h b 70%, Dissolution 8 h N 80%, oating force at 1 h N 2500 N/g, and showed that the pellets can be utilized as a platform for manufacturing
oating force at 9 h N 2500 N/g, then the sweet spots would be gener- a viable gastroretentive controlled-release DDS. The pellets were well
ated as the red area in the plot at the level of A) 6%, B) 10%, and C) 14% characterized, and the effects of various factors on pellet properties
drug load (Fig. 12). Each point on the plot represents a paired value for were regressively correlated. The pellets had excellent bioadhesion, a
HPMC content and SBC percentage. If a representative point changes high and stable oating force, and a capability for controlled drug re-
within the sweet spot area, the setting constraints are still satised. Ap- lease up to 12 h. The dual gastroretentive mechanisms of the pellets
plying this principle in production, compositions might vary because of are highly resistant to stomach physiological activities, which tend to
random or systematic errors, but variable limits should be determined push dosage forms out of the stomach into the intestine. The FEL

Fig. 11. Dissolution proles of experimental formulations and crude API in FaSSGF (SD, n = 3).
 A.Q. Vo et al. / European Journal of Pharmaceutical Sciences 102 (2017) 7184 83

Fig. 12. Illustration of sweet-spot application in QBD design space. A) Low drug load. (B) Medium drug load. (C) High drug load. (D) Constrained criteria.

amorphous SD generated in situ supersaturation that would ultimately Konno, H., Handa, T., Alonzo, D.E., Taylor, L.S., 2008. Effect of polymer type on the disso-
lution prole of amorphous solid dispersions containing felodipine. Eur. J. Pharm.
help the drug absorb more consistently and completely. This study has Biopharm. 70, 493499.
the potential to systematically scale up by applying the design space Lopes, C.M., Bettencourt, C., Rossi, A., Buttini, F., Barata, P., 2016. Overview on
QBD concept. gastroretentive drug delivery systems for improving drug bioavailability. Int.
J. Pharm.
Malode, V.N., Paradkar, A., Devarajan, P.V., 2015. Controlled release oating
multiparticulates of metoprolol succinate by hot melt extrusion. Int. J. Phar. 491,
Acknowledgement 345351.
Marques, M.R.C., Loebenberg, R., Almukainzi, M., 2011. Simulated biological uids with
possible application in dissolution testing. Dissolut. Technol. 18, 1528.
This work was partially supported by Grant Number P20GM104932
Murdande, S.B., Pikal, M.J., Shanker, R.M., Bogner, R.H., 2010. Solubility advantage of
from the National Institute of General Medical Sciences (NIGMS), a com- amorphous pharmaceuticals: I. A thermodynamic analysis. J. Pharm. Sci. 99,
ponent of NIH. The authors also thank the Pii Center for Pharmaceutical 12541264.
Technology for contributions in this project. Newton, J.M., 2010. Gastric emptying of multi-particulate dosage forms. Int. J. Pharm. 395,
28.
Pawar, V.K., Kansal, S., Asthana, S., Chourasia, M.K., 2012. Industrial perspective of
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