International Journal of Pharmaceutics 465 (2014) 169–174

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

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

Evaluation of the resistance of a geopolymer-based drug delivery

system to tampering
Bing Cai, Håkan Engqvist, Susanne Bredenberg ∗
Division for Applied Materials Science, Department of Engineering Sciences, The Ångström Laboratory, Uppsala University, Box 534,
SE-751 21 Uppsala, Sweden

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

Article history: Tamper-resistance is an important property of controlled-release formulations of opioid drugs. Tamper-
Received 2 December 2013 resistant formulations aim to increase the degree of effort required to override the controlled release of the
Received in revised form 12 February 2014 drug molecules from extended-release formulations for the purpose of non-medical use. In this study, the
Accepted 15 February 2014
resistance of a geopolymer-based formulation to tampering was evaluated by comparing it with a com-
Available online 17 February 2014
mercial controlled-release tablet using several methods commonly used by drug abusers. Because of its
high compressive strength and resistance to heat, much more effort and time was required to extract the
Keywords:
drug from the geopolymer-based formulation. Moreover, in the drug-release test, the geopolymer-based
Formulation
Resistance to tampering
formulation maintained its controlled-release characteristics after milling, while the drug was released
Opioids immediately from the milled commercial tablets, potentially resulting in dose dumping. Although the
Abuse tampering methods used in this study does not cover all methods that abuser could access, the results
Oral drug delivery obtained by the described methods showed that the geopolymer matrix increased the degree of effort
Controlled release required to override the controlled release of the drug, suggesting that the formulation has improved
resistance to some common drug-abuse tampering methods. The geopolymer matrix has the potential
to make the opioid product less accessible and attractive to non-medical users.
© 2014 Elsevier B.V. All rights reserved.

1. Introduction commercially marketed products in U.S.: opioid antagonist, non-

sequestered aversive excipients and physical barriers. However,
Extended-release (ER) formulations are designed to control since in most cases of abuse it is necessary to pulverize the
the release of the active pharmaceutical ingredient (API) at a dosage form, the drug formulation with physical barrier that
steady rate for an elongated period. Since ER formulations usu- could create obstacles for pulverization and accordingly provide
ally contain a high dose of the API, they are more attractive to desire therapeutic effects can thwart most of the intentional
abusers than their corresponding immediate-release counterparts formulation manipulation (Anonymous, 2013; Mastropietro and
(Kuehn, 2007; Manchikanti and Singh, 2008; Mansbach and Moore, Omidian, 2012; Stanos et al., 2012). Reformulated OxyContin® and
2006). ER tablets containing oxycodone, for example, are frequently Remoxy® are the two examples of abuse-resistant ER oxycodone
abused because of their euphoric effects (Dunn et al., 2008; Katz that have been approved by U.S. food and drug administration
et al., 2011; Rosenblum et al., 2007). As published by the survey in (FDA). In vitro studies showed that both formulations could
2010, the number of emergency department visits related to the hinder the non-medical use of oxycodone (Anonymous, 2008a,b;
non-medical use of oxycodone increased 152% from 2004 to 2008 Goliber, 2005). Further a number of patents pending and issued
in the United States (Anonymous, 2010a). The controlled release dealing with new abuse deterrent technologies, one example is
of opioid formulations is commonly tampered by crushing, co- U.S. Pat. No. 7955619 that describes a formulation comprising
digesting with alcohol and dissolution in water or other solvents of a core containing opiates with two or more layers of polymer
to facilitate a rapid onset of effect (Anonymous, 2008a). coatings (Shah and Difalco, 2011). The coatings could render the
Three tamper-resistant strategies to prevent inten- drug resistant to extraction and possibly increase the mechanical
tional/unintentional misuse and abuse are currently used in strength of the dosage form. U.S. Pat. No. 8420056 discloses a
formulation comprising thermoplastic polymers, optionally waxes
and other auxiliary substances (Arkenau-Maric et al., 2013). By
∗ Corresponding author. Tel.: +46 18 471 72 42; fax: +46 18 471 35 72. melt extrusion of all the excipients, the formulation exhibits a
E-mail address: susanne.bredenberg@telia.com (S. Bredenberg). breaking strength of at least 500 N. U.S. Pat. No. 8415401 discloses

http://dx.doi.org/10.1016/j.ijpharm.2014.02.029
0378-5173/© 2014 Elsevier B.V. All rights reserved.
170 B. Cai et al. / International Journal of Pharmaceutics 465 (2014) 169–174

a controlled release carrier containing high viscosity liquid carrier Table 1

Molar ratio of the elements in the geopolymer paste.
material and other excipients that could be resistant to extraction
in ethanol and other common household solvents (Yum et al., Elements Molar ratio
2013). Moreover, a lot of more formulations resistant to abuse Si/Al 1.94
have been developed (Bartholomaeus et al., 2012; Bastin and H2 O/Al2 O3 12.31
Lithgow, 2001; Habib et al., 2013; Mastropietro and Omidian, Na2 O/Al2 O3 1.21
2012; Rahmouni et al., 2013; Vaghefi et al., 2014; Webster, 2007).
As the resistance of the product to tampering will never be abso-
published study (Jämstorp et al., 2010). The characterization of the
lute, researchers are endeavouring to find new formulations that
geopolymer is described in Supplementary information.
will further reduce the abuse potential without compromising the
efficacy of the drug administered by tablets or capsules and to
provide alternative formulations during therapy. 2.3. Physical manipulation
Geopolymer is a porous ceramic material composed of the three-
dimensional polysialate framework containing SiO4 and AlO4 . Laboratory-based manipulation and extraction studies are
Depending on the different compositions and synthesis condi- required by the FDA to estimate the product’s abuse potential
tions, geopolymer can exhibit a variety of porosity and mechanical (Anonymous, 2010b, 2013). The tests for resistance to tampering
strength. Geopolymer has been suggested for bone restoration aim to evaluate the difficulty with which the controlled release
because of the bioactivity of amorphous silicate networks. That of the formulation can be bypassed or compromised to achieve
study showed that the geopolymer material with high porosity, rapid or immediate release of the drug. The following tests have
good biocompatibility and little Al3+ leakage has a valuable poten- been used in previously published studies to simulate the methods
tial in biomedical application (Oudadesse et al., 2007). In another commonly used by those intending to access the product for non-
work, geopolymer has been evaluated as the matrix material of oral medical purposes (Anonymous, 2008a, 2013; Fadda et al., 2008;
controlled-release opioids formulation because of its advantageous Roth et al., 2009): physical manipulation using crushing/milling,
properties: adjustable porosity, good mechanical strength and low several drug extraction methods ranging from relatively simple
solubility in water (Forsgren et al., 2011; Jämstorp et al., 2010). In to sophisticated, thermal treatment and drug release in ethanol-
the study by Jämstorp et al. (2012), the effect of pellet size on the containing media.
drug release was studied using different drugs and evaluated by the As crushing and milling are common methods of obtaining fast
finite element method. These studies found that the content of Si, onset of effect, resistance to grinding is an important attribution
Na and water in geopolymer matrix affect its porosity, mechanical of tamper-resistant formulations. In this study, both formulations
stability and drug release rate. In addition the drug release rate and were crushed using two spoons and, a more advanced option,
the diffusion was dependent on the drug molecule size and solu- milled with a mortar and pestle for 15 min (Anonymous, 2008a,b).
bility, drug distribution in the matrix and the pellet size. However, Since the particle size distribution following each mode of physical
the resistance of geopolymer-based formulations to tampering has manipulation can influence the rate of opioid release, the size of the
not yet been verified. remaining particles was estimated from scanning electron micro-
This study aims to evaluate the resistance of a geopolymer- scope (SEM) pictures obtained using a Leo 1550 FEG microscope
based ER formulation (denoted as Formulation A) to tampering by (Zeiss, Germany). The residual particles obtained by both modes
comparing it with a marketed controlled-release oxycodone tablet of physical manipulation were then used in extraction and dis-
(denoted as Formulation B) with regard to their physical integrity, solution studies. To further evaluate the formulations on physical
ease of extraction and dissolution performance. manipulation, both formulations were milled using a coffee grinder
(KSW coffee grinder 3306, Clatronic, Germany) as it is technique
commonly used by abusers for size reduction.
2. Materials and methods
2.4. Solvent extraction
2.1. Materials
Chemical extraction could dissolve the essential ER excipients
Kaolin, fumed silica (SiO2 7 nm particles), reagent grade sodium in the intact or manipulated formulations, allowing an abuser to
hydroxide (NaOH), monopotassium phosphate (KH2 PO4 ), 37% fum- bypass the drug’s abuse-deterrent properties. The extraction tests
ing hydrochloric acid (HCl) and 99.5% ethanol were purchased from
Sigma–Aldrich (Stockholm, Sweden). The enteric-coating polymer
Eudragit® L100-55 (Evonik industries, Germany) was a gift from
Orexo AB, Sweden. Oxycodone Orion® infusion solution (10 mg/mL,
Orion pharma) and OxyContin® tablets (5 mg, Mundipharma) were
purchased from Apoteket AB, Sweden.

2.2. Geopolymer synthesis

Metakaolin was obtained by heating kaolinite at 800 ◦ C for 2 h.

Sodium silicate solution was prepared by dissolving NaOH and SiO2
in the oxycodone hydrochloride infusion solution under thorough
mixing. A homogeneous geopolymer paste was prepared by mix-
ing the metakaolin, sodium silicate solution and enteric-coating
polymer (4.35 wt.%). The composition of the geopolymer paste is
shown in Table 1. The geopolymer paste was moulded into pel-
lets (1.5 mm diameter × 1.5 mm height) and cylindrical rods (6 mm
diameter × 12 mm height). The procedure for synthesizing Formu-
lation A is illustrated in Fig. 1 and described in detail in a previously Fig. 1. Schematic drawing of the synthetic process for Formulation A.
 B. Cai et al. / International Journal of Pharmaceutics 465 (2014) 169–174 171

were performed in triplicate with the same total drug-to-solvent Table 2

The equations for mathematical models used to analyze the dissolution profiles.
volume ratio for both formulations: 1 mg to 20 mL. Formulations
A and B and their crushed/milled particles were placed in the fol- Model type Equation
lowing solvents: ethanol-aqueous solution (20 and 40% ethanol, Mt
 Mt
  Mt

Higuchi (cylindrical model) + 1− ln 1 − = KH t
ambient temperature), distilled water (50 ◦ C and 70 ◦ C), 0.1 M HCl M∞

M∞ M∞

solution (pH 1, ambient temperature), and NaOH solution (pH 12, Mt 3

 Mt
2/3 
Higuchi (spherical model) M∞
− 2
1− 1− M∞
= −KH t
ambient temperature) (Anonymous, 2008a,b, 2010b, 2013; Goliber,
2005). Solvents with 40% or 20% ethanol simulated common alco- Hopfenberg (cylindrical model)
Mt
M∞
= 1 − [1 − KHO t]
2

holic drinks and heated water simulated extraction at elevated Mt 3

Hopfenberg (spherical model) M∞
= 1 − [1 − KHO t]
temperatures. The solutions at pH 1 and pH 12 represented the
acidic and alkaline household solvents. Aliquots (1 mL) were with-
drawn from the extracted solutions after 2 h. The concentrations of
oxycodone hydrochloride in the solutions were analyzed using iso-
cratic reversed-phase high-pressure liquid chromatography (HPLC) surface-eroding (Hopfenberg model) (Costa and Sousa Lobo, 2001;
with a photodiode array detector (Waters, Corp., Milford, MA, USA) Siepmann and Siepmann, 2012). The drug release profile of intact
and a YMC-Triart C18 column (2.0 mm ID × 12 mm, 3 ␮m; YMC, and milled formulations were approximated with the cylindrical
Japan). The fraction of drug released was calculated from the total and spherical model, respectively (Siepmann and Siepmann, 2012).
drug content in the formulation. Mt and M represents the amount of drug released in time t and infin-
ity, respectively. KH and KHO are the release constants for Higuchi
and Hopfenberg, respectively. The correlation coefficients were cal-
2.5. Drug-release characteristics
culated from linear regression plots according to the equations. The
fitting with R2 that approaches 1 is regarded as a good fit to the
The in vitro drug-release characteristics are important when
model.
comparing different formulations. The drug-release characteristics
of Formulations A and B and their milled particles were evaluated in
triplicate in a USP 2 dissolution apparatus (Sotax AG, Switzerland)
at 37 ◦ C with a paddle stirring rate of 50 rpm for 24 h. The extraction 3. Results
tests were performed with the same total drug-to-solvent volume
ratio for both formulations: 1 mg to 80 mL. Samples were placed 3.1. Physical manipulation
in the dissolution media (400 mL) at pH 1, pH 6.8, pH 1 with 5%
ethanol or pH 1 with 40% ethanol. The buffers were prepared using After manually crushing with two spoons, Formulation B was
KH2 PO4 , NaOH or HCl in de-ionized water to obtain these pH values. easily granulated into fine grains, while Formulation A was difficult
pH 1 and pH 6.8 media simulated gastric and intestinal fluid, while to crush, resulting in large fragments and no fine powder (Fig. 2c
pH 1 media at the two ethanol concentrations simulated the co- and d). By using the coffee grinder, which is often used by abusers,
digestion of the drug with alcoholic drinks (Anonymous, 2008a,b; the size distributions of the debris of Formulations A and B were
Mastropietro and Omidian, 2012; Stanos et al., 2012; Webster et al., similar (Fig. 2e and f). When more advanced milling with a mortar
2011). During the release tests, aliquots (1 mL) were withdrawn and pestle was used, Formulation B was easily milled into a fine
from the dissolution bath by a sampling tube at predetermined time powder within 2–3 strokes. The residual particles of milled Formu-
intervals. The concentration of drug in the aliquot was analyzed lation B were mostly less than 200 ␮m in diameter (Fig. 2h). Milling
using a UV/Vis spectrophotometer (Shimadzu 1800, Japan). Formulation A into particles of a similar size to those of milled For-
The drug-release data were analyzed using Higuchi and Hopfen- mulation B (Fig. 2g and h) required much more effort and at least
berg model to clarify the kinetics, see Table 2. The two models 15 min. The particles obtained using mortar and pestle were smaller
were based on drug release via diffusion (Higuchi model) or compared to those obtained by milling using the coffee grinder.

Fig. 2. The images showing the size distribution of the particles from physical manipulated Formulations A and B. The spacing of the grid in the background is 1 mm. Images
(a) and (b) show intact Formulations A and B, respectively. Images (c) and (d) show Formulations A and B, respectively, after crushing between two spoons. Images (e) and (f)
show Formulations A and B, respectively, after grinding by coffee grinder. Images (g) and (h) show Formulations A and B, respectively, after milling with a mortar and pestle.
172 B. Cai et al. / International Journal of Pharmaceutics 465 (2014) 169–174

In 70 ◦ C water, intact Formulation A and its crushed particles

were more resistant to extraction than intact or crushed Formu-
lation B (mean 30% and 35% extracted from Formulation A versus
49% and 84% from Formulation B). Because of the small particle
sizes in both milled formulations, both Formulation A and Formu-
lation B released more than 90% of the drug content after extraction
in 70 ◦ C water. The results were similar in 50 ◦ C water: intact For-
mulation A released 18% of the total drug content versus 55% for
intact Formulation B; crushed Formulation A released 23% versus
78% for crushed Formulation B; and, in this case, milled Formulation
A released 51% versus 93% for milled Formulation B.
A greater fraction of the total drug content was released from
intact Formulation A than from intact Formulation B at pH 1. How-
ever, Formulation A was more resistant to drug extraction at this pH
after crushing (27% released from Formulation A versus 87% from
Formulation B). The milled formulations performed similarly at pH
1. In an alkaline solvent, drug extraction was similar for the intact
Fig. 3. The fractions of oxycodone content extracted in six solvents after 2 h, from
formulations. However, 15% of the drug content was released from
Formulations A and B and their crushed and milled particles. The error bars denote crushed Formulation A versus 63% for crushed Formulation B at
the confidence intervals for three independent samples. pH 12. The extraction results for the milled samples were also dis-
parate: 58% was released from milled Formulation A and 86% from
milled Formulation B. In general, samples released more drug at
3.2. Solvent extraction pH 1 but less drug at pH 12, probably because of the pH-dependent
drug solubility (Kuo et al., 1989).
The fractions of oxycodone released from Formulations A and B
and their crushed or milled particles during 2 h in various extrac- 3.3. Drug-release characteristics
tion solvents are shown in Fig. 3. In the ethanol-containing solvents,
both intact Formulations were equally resistant to extraction of the Intact Formulation A and intact Formulation B released the
drug; however, it was more difficult to extract oxycodone from the drug continuously, liberating 50% of the drug after 2 h in all media
crushed particles of Formulation A than from those of Formulation B (Fig. 4a–d). The milled Formulation A had released less than 70%
(Formulation A released 15% of the drug content while Formulation of the drug after 2 h in all media, while the milled Formulation B
B released more than 80%). The fraction of drug released was simi- had liberated almost all the drug within 30 min (Fig. 4a–d). There
lar for the two milled formulations in ethanol-containing solvents were no significant differences in release behaviours between the
(nearly 95% of the drug content was released). The released frac- formulations at pH 1, pH 6.8 or pH 1 with 20% ethanol for all intact
tion was slightly lower in 20% ethanol solution than in 40% ethanol, and milled samples (Fig. 4a–c). The medium containing 40% ethanol
probably because of the difference in the solubility of oxycodone in promoted release from Formulation A slightly but the sustained
water and ethanol (Kalso, 2005). release was still maintained (Fig. 4d).

Fig. 4. Drug release profiles over 24 h for Formulations A and B and their milled particles. The drug release tests were performed at (a) pH 6.8, (b) pH 1, (c) pH 1 with 5%
ethanol, and (d) pH 1 with 40% ethanol. The error bars denote confidence intervals for three independent samples.
 B. Cai et al. / International Journal of Pharmaceutics 465 (2014) 169–174 173

Table 3
The release constants and coefficients of determination (R2 ) of the fitting of the release profiles for the Higuchi and Hopfenberg models.

Samples Media Higuchi Hopfenberg

KH R2 KHO R2

Formulation A pH 6.8 0.046 0.9723 0.024 0.958

pH 1 0.065 0.997 0.031 0.983

Milled Formulation A pH 6.8 −0.063 0.982 0.031 0.905

pH 1 −0.031 0.946 0.023 0.895

Formulation B pH 6.8 0.094 0.969 0.046 0.945

pH 1 0.080 0.995 0.048 0.956

Milled Formulation B pH 6.8 −0.001 0.506 0.003 0.343

pH 1 – 0.291 0.003 0.307

The release profiles at pH 1 and pH 6.8 were evaluated to under- heating. This indicates that it is easier to compromise the polymer
stand the main factors controlling release from Formulations A and matrix than the ceramic one using heated water.
B (Table 3). Overall, the release behaviours of Formulation A fitted The intact geopolymer-based Formulation A released 26% more
the Higuchi model best, while they fitted the Hopfenberg model oxycodone than the commercial Formulation B at pH 1. However,
as well. The release profile of the milled Formulation A also fitted after crushing, Formulation A was more resistant to drug extrac-
the Higuchi model. Intact Formulation B fitted the Higuchi model; tion than Formulation B. The increased fraction released in pH 1
however, because milled Formulation B released over 80% of its from the intact Formulation A may have been due to reductions
drug content within 15 min, its fast release profile did not fit any in the drug–matrix interaction and matrix structure transforma-
model. tion (Jämstorp et al., 2010). Changes to the polymer composition
in Formulation A might help to improve its resistance to acidic
conditions.
4. Discussion The drug-release tests were performed to compare the release
of oxycodone from the intact and physically manipulated Formu-
In this study, a ceramic material has been explored as matrix lation A and Formulation B in various media. The results showed
material for tamper-resistant opioid dosage form and the tamper- that both intact formulations fitted the Higuchi model, indicating
resistance of the geopolymer-based formulation (Formulation A) that diffusion was the rate-limiting step for drug release from both
has been compared with a commercially marketed oxycodone ER formulations. This concurred with previous findings that the main
tablet (Formulation B). These bench studies evaluated the resis- rate-limiting factor for geopolymer drug carriers is the diffusion
tance of Formulations A and B to common methods of physical of the drug out of the matrix (Jämstorp et al., 2011). After milling,
and chemical tampering. Resistance to crushing and milling is an Formulation A released the drug faster than the intact formulation
important attribute, as these physical manipulation methods are because of its increased surface area, but the release profiles most
commonly used to prepare the dosage form for extraction of the resembled the Higuchi model. This indicated that control of drug
active ingredients. Despite the high power and stainless steel blade, release was still maintained for the small geopolymer particles. In
the electronic coffee grinder could not provide a uniformed grind- contrast, Formulation B released almost all the drug content within
ing as manual milling, which led a larger size distribution. As shown 30 min and was associated with a higher risk of dose dumping.
in Fig. 2, Formulation A had higher resistance to the physical defor- These results indicate that milling could compromise the controlled
mation. The high strength geopolymer matrix in Formulation A was release of oxycodone from Formulation B and could thus induce
designed to increase the difficulty of mechanical manipulation. For- immediate release of the drug.
mulation B, which had a mechanically weaker polymeric matrix,
was readily crushed into fine grains with much less effort and
time. Although the methods used could not represent all tampering 5. Conclusions
method used by the abusers, this result gave a brief understanding
that the geopolymer-based formulation has the potential to reduce As abuse of opioid formulations emerged as public problem, a
the likelihood of the product being mechanically manipulated and lot of development on tamper-resistant dosage form has been done.
could dissuade non-medical users from crushing or milling the for- Polymers have been used in most of current tamper-resistant for-
mulation. mulations to thwart intentional crushing and extraction of the drug
A range of extraction solvents was used to study the drug formulation. However, this study presents an alternative mate-
extractability for both formulations. In general, the outcomes for rial to these polymers. Previous studies have shown that as the
both intact formulations were comparable; similar amounts of oxy- drug release mechanism from geopolymer was mainly by diffu-
codone were released, other than at pH 1, which will be discussed sion, the drug release rate of the formulations comprise geopolymer
below. However, crushed Formulation A was much more resis- as matrix could be adjusted by the porosity and composition of
tant to extraction than the corresponding commercial formulation. geopolymer. With high mechanical strength and low solubility
Because of its high resistance to grinding as mentioned in Section in water and organic solvents, geopolymer has the potential to
3.1, Formulation A formed larger particles after crushing and thus protect the drug with abuse-potential from intentional tamper-
was able to retain the drug for longer during extraction testing. ing. This study evaluated and compared the abuse potential of a
Heated water simulated extraction at elevated temperatures. geopolymer-based oxycodone delivery system and a commercial
Less oxycodone was released from the geopolymer-based formula- oxycodone formulation. The results showed that the geopolymer-
tion than from the commercial formulation under these conditions. based formulation was mechanically stronger and required much
Polymers in the Formulation B matrix became more elastic and flex- more effort and time to grind it into a fine powder than the commer-
ible at higher temperatures, thus providing larger spaces through cial formulation. Because of its good physical integrity, crushing the
which the drug molecules could diffuse. In contrast, the ceramic geopolymer-based formulation resulted in larger fragments than
matrix of Formulation A remained rigid and inflexible even after those obtained on crushing the commercial formulation, which
174 B. Cai et al. / International Journal of Pharmaceutics 465 (2014) 169–174

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