Melts of Octaacetyl Sucrose as Oral-Modified Release Dosage Forms for Delivery of Poorly Soluble Compound in Stable Amorphous Form
Melts of Octaacetyl Sucrose as Oral-Modif ied Release Dosage Forms for Delivery of Poorly Soluble Compound in Stable Amorphous Form
The presented work describes the formulation and characterization of modified release glassy solid dosage forms (GSDFs) containing an amorphous nifedipine, as a model BCS (Biopharmaceutical Classification System) class II drug. The GSDFs were prepared by melting nifedipine together with octaacetyl sucrose. Dissolution profiles, measured under standard and biorelevant conditions, were compared to those obtained from commercially available formulations containing nifedipine such as modified release (MR) tablets and osmotic release oral system (OROS). The results indicate that the dissolution profiles of the GSDFs with nifedipine are neither affected by the pH of the dissolution media, type and concentration of surfactants, nor by simulated mechanical stress of biorelevant intensity. Furthermore, it was found that the dissolution profiles of the novel dosage forms were similar to the profiles obtained from the nifedipine OROS. The formulation of GSDFs is relatively simple, and the dosage forms were found to have favorable dissolution characteristics.
acetylated saccharides; modified release; sustained release; amorphous drugs; biorelevant dissolution stress test; oral osmotic system
The bioavailability of orally administered drugs is very
often limited by their solubility. This applies mainly to BCS
class II and IV compounds whose overall absorption may be
limited by their low solubility in water (
technological approaches can be applied to overcome this
problem. These include processing techniques to improve the
solubilization parameters of the active pharmaceutical
ingredient (API). Most commonly applied operations involve the
optimization of API particle size or other means of particle
engineering, improvement of wetting behavior, use of
surfactants, preparation of solid dispersions, and the formulation
of self-emulsifying or self-micro-emulsifying systems (3).
Furthermore, the preparation of the APIs in the
amorphous form is well known although challenging (
Amorphous substances show altered physico-chemical
properties in comparison to their crystalline counterparts (
Consequently, they often exhibit improved solubility,
enhanced dissolution rate, and improved bioavailability (
). Amorphization can be achieved by various routes, i.e., (i)
solvent evaporation, (ii) milling, (iii) freeze- or spray drying,
and (iv) quench cooling. These techniques are widely applied
in the preparation of immediate release formulations.
However, amorphous substances are often labile and therefore
stability issues frequently become the major challenge of the
formulation efforts. One of the opportunities to stabilize
amorphous APIs is the addition of excipients to suppress
recrystallization: Examples of materials to suppress
recrystallization are polymers and low molecular weight compounds,
such as amino acids, polyhydroxy alcohols, traditional as well
as modified saccharides
Recently, the importance of acetylated derivatives of
saccharides has been emphasized (
). These substances
are cost-effective and are widely used in the food industry.
One example of a modified saccharide is acetylated starch
(E1451), which is used as a binding agent. Acetylated starch is
classified by the Food and Drug Administration (FDA) as a
Generally Recognized as Safe (GRAS) material. Numerous
investigations regarding the use of various sugar derivatives,
i.e., acetylated sucrose, glucose, maltose, galactose, to
stabilize amorphous forms of drugs, such as indomethacin,
itraconazole, and nifedipine have been published (
Solid dispersions composed of amorphous APIs have been
obtained by melting with appropriate ratios of active
substances and modified saccharides followed by rapid cooling.
The binary solid dispersions can be subsequently processed to
the final solid dosage forms easily.
Controlled delivery of BCS class II drugs often requires
improved solubility and stable drug release for the
appropriate time period. Commercially available formulations, e.g.,
polymer matrix systems with erosion-driven drug release or
oral osmotic systems (OROS) with osmotically controlled
drug delivery, involve various mechanisms to obtain
appropriate drug dissolution. Besides indisputable advantages of
such formulations, there are also some drawbacks with
regards to high costs and complexity of the systems, limited
usefulness for application with poorly soluble APIs, or risk of
toxicity increase due to dose dumping (e.g., in the case of
coating perforation (
)). For these reasons, there is
still need to contemplate novel strategies for controlled
delivery of poorly soluble drugs.
Nifedipine (NIF) is a widely used calcium channel
blocker, whose efficiency and tolerability have been
confirmed in a number of studies (
). Both forms of NIF,
crystalline and amorphous, are available and the latter one
shows significantly improved solubility kinetics and saturation
solubility, but it is physically unstable. Numerous researchers
have investigated the pharmacokinetics of oral as well as
parenteral formulations. It has been demonstrated that a
rapid increase of nifedipine plasma concentrations results in
an increased occurrence of undesirable effects, e.g., hearing
). Consequently, it has become evident that
improvement of efficiency and safety of the cardiovascular
diseases treatment with nifedipine is required (19).
In a pre-formulation study, nifedipine has been used as a
typical BCS class II drug, which could be utilized as model for
development of novel techniques of controlled drug delivery
). The study has outlined the advantages of the application
of octaacetyl sucrose for the stabilization of amorphous
nifedipine. It has been shown that higher concentrations
(> 50% by weight) of modified disaccharides sufficiently
suppress recrystallization. Moreover, it has been found that
the amorphous form of API remained stable even after 1 year
of storage under room conditions (
). In this context,
application of acetylated saccharides in the formulation seems
to be a promising option (
To date, the use of acetylated carbohydrates has been
focused on the development of immediate release
). However, their application in modified release
dosage forms has not been sufficiently investigated.
Therefore, the goals of the study were:
– Development and performance assessment of
glassy solid dosage forms (GSDFs)—oral matrix modified
release dosage forms—for delivery of poorly soluble
compound (nifedipine) in stable amorphous form,
– Comparing the developed formulation with
commercially available nifedipine products in simulated
gastrointestinal tract conditions in vitro and to relate them
to in vivo literature data.
The presented study follows pre-formulation
investigations performed by the members of our group (
Materials and Methods
Preparation of GSDFs Containing Glassy Nifedipine and
Nifedipine reference standard (batch number 516A051),
sucrose octaacetate (C28H38O19), pepsin (USP grade), and
pancreatin (USP grade) were supplied by Sigma Aldrich
(Steinheim, Germany). High-purity water used in analytical
procedures was obtained from a Millipore Milli-Q plus
ultrapure water system (Bedford, MA, USA). HPLC grade
methanol was purchased from VWR International
(Fontenay-sous-Bois, France). All other chemicals and
reagents of analytical grade were provided by VWR
Nifedipine and acetylated sucrose (30 and 150 mg,
respectively, for each single matrix) were weighed and
transferred to conical silicone molds and gently mixed.
Subsequently, the forms were heated up to 190 ± 5°C in an
oil bath (IKA® RCT basic, IKA®-Werke GmbH, Staufen,
Germany) and the powder blends were molten for 10 min
under visual inspection. After melting, the molds were
removed from the oil bath and cooled down at room
temperature (± 22°C). The conical glassy nifedipine matrices
(4 mm height, 6 mm diameter at the bottom each) were
retrieved, weighed, and stored at room temperature under
protection from light.
For comparison, the following commercial formulations
were used: GITS Adalat OROS (Bayer, Berlin, Germany)
and Nifedipine Sandoz (Sandoz, Kundl, Austria). Each of the
commercial formulations contained 30 mg of the drug, i.e.,
the same dose as for developed glassy melt formulation.
Solubility of Crystalline Nifedipine and its Amorphous Form from Solid Dispersion with Acetylated Sucrose
The solubility of crystalline nifedipine and nifedipine in
solid dispersions with acetylated sucrose was determined
using USP phosphate buffer (pH 6.8). For this purpose, the
powders (~ 10.5 mg) were transferred to glass vials (n = 3)
containing a magnetic stirring bar (3 mm in diameter, 7 mm in
length each). After addition of 6 mL preheated medium
(37 ± 0.5°C), the samples were stirred for 24 h at 37 ± 0.5°C,
300 rpm (IKA® RCT basic, IKA®-Werke GmbH, Staufen,
Germany). Samples of 200 to 300 μL were withdrawn with a
2-mL polyethylene syringe (Injekt® Solo, B. Braun
Melsungen AG, Melsungen, Germany) and filtered through
a PTFE-filter (CHROMAFIL® Xtra H-PTFE-20/13,
Macherey-Nagel GmbH & Co. KG, Düren, Germany).
Samples were taken at 5, 10, 15, and 30 min as well as 1, 2, 3,
4, 6, and 24 h after addition of dissolution media.
Subsequently, 200 μL of the supernatant was diluted in 600 μL
HPLC solvent (methanol: water 50:50, pH 3.0) and
transferred to HPLC vials for chromatographic analysis. All
procedures described were conducted under light protection
to avoid UV degradation of binary mixtures and reference
The concentration of nifedipine in solution was
determined using a Merck-Hitachi Elite LaChrom HPLC system
(Merck, Darmstadt, Germany) equipped with L-2130 Pump,
L-2200 autosampler, L-2400 UV Detector, and a Jetstream II
Plus column oven. A LiChrospher 100 RP-18 (5 μm)
125 × 4.0 mm column (Merck Millipore, Darmstadt,
Germany) was used to achieve chromatographic separation. The
mobile phase consisted of mixture of methanol and water
(65:35 v/v) was adjusted to pH 3.0 with orthophosphoric acid
(85 vol%). Samples were separated at a flow rate of 0.8 mL/
min and a column temperature of 35°C. A partial loop with
needle overfill option was used, and the injection volume was
kept at 50 μL for all experiments. The UV detection of NIF
was carried out at wavelength α = 238 nm. The acquired data
were processed using the Clarity software (Data Apex,
Prague, Czech Republic).
Standard Dissolution Tests
The dissolution tests were performed using a USP
apparatus 2 (ERWEKA DT80, ERWEKA GmbH,
Heusenstamm, Germany, PT-DT 7, PharmaTest, Hainburg,
Germany) at rotational speed of 100 rpm at 37.0 ± 0.5°C. The
studies of NIF dissolution were carried out in the following
dissolution media: (a) HCl Solution pH 1.0 with 0.1% m/v
SDS (sodium dodecyl sulfate); (b) USP acetate buffer pH 4.5
with 0.1% m/v SDS; and (c) USP buffer solution for
nifedipine extend release tablets pH 6.8.
The amounts of the drug dissolved were determined
using online UV-Vis spectroscopy. The samples were filtered
through PES (polysulfone) filter with a pore size of 0.8 μm
(Sartorious, Göttingen, Germany) and analyzed.
Quartz cuvettes of 10 mm path length (Hellma,
Müllheim, Germany) were used with a UV 1602
spectrophotometer (Shimadzu, Duisburg, Germany) and an Agilent 8543
spectrophotometric system (Agilent, Santa Clara, USA) with
the photometers set to differential mode at two wavelengths
of λ = 330 nm for the NIF signal and λ = 450 nm for the
All dissolution experiments and analytical procedures
were performed under light protection. For evaluation of
water penetration into the GSDFs the dissolution
experiment was repeated with addition of 0.1% methylene blue
into the medium. After 4 h of experiment, the tablets were
withdrawn from the solution and photographed. The images
were performed using stereomicroscope OPTA-TECH
Biorelevant Dissolution Stress Test
Simulation of the mechanical stresses of the maximal
physiological intensity was performed using the biorelevant
dissolution stress test device. A detailed description of the
device is given elsewhere (
). In the following, a brief
overview is provided. The dissolution stress test device
enables the exposition of the specimens to repeating
sequences of movements, pressure waves, and phases of rest
as they may act on extended release dosage forms during
gastrointestinal transit. The apparatus used in this study was
driven in two simple stress sequences of agitation within the
boundaries of conditions observed in vivo.
Both sequences comprised of phases of a dynamical
stress caused by rotation of the central apparatus axis at
100 rpm over a period of 1 min followed by three symmetrical
pressure waves of 6 s duration at 300 mbar. The stress phases
were repeated every 20 min in case of the first (19+1)
sequence and every 60 min in case of second (59+1)
Studies of NIF dissolution were carried out in the
following separate dissolution media: HCl solution pH 1.0
with 0.1% m/v sodium dodecyl sulfate (SDS), USP acetate
buffer pH 4.5 with 0.1% m/v SDS, and USP buffer solution
for nifedipine extend release tablets pH 6.8.
The impact of the surfactant concentration on the
dissolution of GSDFs was investigated under 19+1 stress
sequence using pH 6.8 buffer solution for nifedipine extend
release tablets containing 0.5 or 1.0% of SLS. The impact of
physiological surfactants on the dissolution profiles was
investigated using fed-state simulated intestinal fluid
The amount of the drug dissolved was determined using
online UV-Vis spectroscopy as described in the previous
section. All dissolution experiments and analytical procedures
were performed under light protection.
Processing and Comparison of the Dissolution Profiles
The dissolution profiles obtained under standard and
stress test conditions were processed using commercial
software (Axum 5.0, MathSoft, Inc., Cambridge, MA,
USA). The mean dissolution profiles obtained under the
different test conditions were analyzed using coefficients
of the linear regression as well as similarity coefficient
Robustness of GSDFs Towards Digestive Enzymes
The impact of pepsin and pancreatin was qualitatively
investigated by incubating the GSFDs in 250 mL of USP
simulated gastric fluid test solution (USP SGF TS) and USP
simulated intestinal fluid test solution (USP SIF TS). USP
phosphate buffer pH 6.8 with 0.1% surfactant was used as a
reference medium allowing the determination of the potential
impact of the digestive enzymes on the durability of the
SGDFs. The incubation was performed in beakers (∅ 10 cm,
800 mL volume) using a shaking water bath (Julabo SW22,
Julabo GmbH, Seelbach, Germany) at 37°C and 30 cpm over
4 h. After each hour of experiment, the tablets were
withdrawn from the solution, photographed using a calibrated
EOS 60D digital camera (Canon, Tokyo, Japan) and
processed using commercial software (Google Nik Collection,
Google, Mountain View, USA)
GSDFs containing nifedipine and acetylated sucrose
were transparent, of yellow color, and had a smooth surface.
The photographic representation of the formulation is given
in Fig. 1. The GSDFs contained neither pores nor air
inclusions, which was confirmed by visual inspections using
Prepared dosage forms fulfilled the pharmacopoeial
requirements concerning uniformity of content and mass
uniformity. The NIF content variability was about 0.5%, and
the weight variation of the GSDFs did not exceeded 0.3%.
Solubility Study of Crystalline Nifedipine and its Amorphous
Form from the Solid Dispersion with Acetylated Sucrose
The solubility of the crystalline form of nifedipine and
nifedipine from the solid dispersion with acetylated sucrose
was determined using the USP phosphate buffer (pH 6.8).
The results of the solubility study are given in Fig. 2.
In comparison to the nifedipine reference substance, the
solubility of NIF from solid dispersion was enhanced slightly.
The crystalline nifedipine reached a saturation concentration
of 10 μg/mL within approximately 90 min of incubation. The
saturation solubility was maintained for 6 h. In case of the
solid dispersion of amorphous nifedipine with acetylated
sucrose, fast dissolution of nifedipine and supersaturation of
the drug solution was observed within the first 60 min of
incubation at a concentration of the API corresponding to
approximately 17 μg/mL. Supersaturation above 16 μg/mL
was maintained for 3 h. Subsequently, a slight decrease in the
concentration of nifedipine down to approximately 15 mg/mL
occurred. Noticeably, the API concentration achieved at
360 min with the solid dispersion was still approximately
40% higher than in the case of crystalline drug. The
determined saturation solubilities of nifedipine amounted to
approximately 14 and 10 μg/mL for the solid dispersion and
crystalline drug, respectively.
Standard Dissolution Tests
The results of standard dissolution tests are given in the
Fig. 3a–c. Dissolution profiles of glassy solid dispersions of
nifedipine with acetylated sucrose are shown in Fig. 3a.
Dissolution of nifedipine in all media was linear with a
constant dissolution rate ranging from 3.9 to 4.1%/h. The
slopes of the dissolution profiles as well as the corresponding
coefficients of linear regression determined on mean
dissolution profiles are shown in Table I. During the dissolution
tests, the formulations did not swell or erode. Moreover, no
lag phase was observed. Such a behavior may suggest that the
dissolution rate is dependent on the surface area of the
investigated formulation. This observation could be of great
importance, since it showed that dissolution of nifedipine
could be controlled and optimized solely by manipulation of
the surface of studied formulations (
Dissolution kinetics of the MR tablets showed a
significant dependency on the pH of the dissolution medium as
shown in Fig. 3b. The dissolution rate was the fastest at pH 6.8 at
which 50 to 80% of the drug was dissolved approximately
after 6 to 8 h. Slower drug release was observed in buffer
solutions at pH 4.5, where 50 to 80% of the active substance
was dissolved after approximately 16 to 20 h. At pH 1.0,
the dissolution was the slowest and reached a maximum of 50%
within approximately 22 h. Visual inspection performed
during the dissolution tests revealed pH-dependent swelling
and erosion of the tablets.
The dissolution profiles of Adalat OROS GITS 30 mg
in different pH are given in Fig. 3c. The dissolution profiles
of the GITS system show a characteristic lag phase of up to
2 h in contrast to the dissolution profiles for glassy solid
dispersions. The dissolution profiles for all test specimens of
the OROS formulation were very similar regardless of the
pH of the medium. Dissolution rate estimated over the
entire dissolution profiles, amounted to 4.2%/h, and
complete dissolution of the drug load was achieved within 23 h.
Biorelevant Dissolution Stress Tests
The results of the biorelevant dissolution experiments
performed under stress sequencies (19+1 and 59+1), using
USP phosphate buffer for nifedipine ER tablets pH 6.8 are
presented in Fig. 4a–b. In the case of nifedipine-acetylated
sucrose GSDFs as well as Adalat OROS GITS, the
mechanical agitation under both stress regimens did not cause dose
dumping of the drug. Similarly to the standard dissolution
tests for Adalat OROS GITS, a 2-h lag time was observed for
that formulation, while no lag time was witnessed for the
developed formulation with acetylated sucrose. The
dissolution profiles of both formulations were closely to linear and
slightly higher for OROS GITS. The calculated dissolution
rates amounted to approximately 4.9 and 4.2%/h for Adalat
OROS GITS and solid dispersions of nifedipine, respectively.
Visual inspection performed during the dissolution stress tests
revealed that the nifedipine formulation with modified
sucrose was highly resistant to mechanical agitation of
physiological range and did not erode or deform under
applied mechanical stresses.
In contrast, the dissolution profiles of MR tablets
clearly indicated the susceptibility of the matrices to
mechanical agitation within the physiological range. Each
simulated stress sequence effected rapid erosion of the
tablet matrices and following dose dumping. In this case,
dissolution was completed within approximately 2.3 h under
19+1 sequence (stress phase repeated every 20 min) and
4.2 h under 59+1 sequence (stress phase repeated every
The stress tests of GSDFs performed in dissolution
media containing 0.5 and 1% SLS as well as FeSSIF under
19+1 stress sequence led to similar dissolution profiles as
obtained using USP buffer for nifedipine tablets with 0.1%
SLS. The calculated F2 values were ≥ 93. The results are
given in Fig. 5.
Robustness of GSDFs Towards Digestive Enzymes
The visual inspection of the GSDFs performed during
the incubation in USP phosphate buffer for nifedipine tablets
with 0.1% SLS, USP SGF TS, and USP SIF TS yielded no
differences in visual appearance. During the incubation in
these dissolution media, the formulations were not digested,
apparently did not swell or erode. The results of the visual
inspections are given in Fig. 6.
Stability—Result of Pre-Formulation Study
The comprehensive studies on solid dispersions of NIF
with four representative acetylated saccharides, with the use
of several experimental methods, such as DSC (differential
scanning calorimetry), FTIR (Fourier transform infrared
spectroscopy), XRD (X-ray diffraction), BDS (broadband
dielectric spectroscopy) as well as molecular dynamic
simulations have been carried out in the pre-formulation phase of
the study and are described elsewhere (
). It has been shown
that in contrast to acetylated monosaccharides, modified
disaccharides affect crystallization of active substance both
above and below the glass transition temperature (Tg). It has
been found that the activation barrier for the crystallization of
nifedipine increases significantly in binary mixtures composed
of acetylated disaccharides for the experiments carried out
above Tg. The long-term studies on the physical stability of
investigated solid dispersions stored in the close vicinity and
below Tg revealed that for the higher amount of API,
nifedipine tends to re-crystallize from each solid dispersion,
while for the higher content of excipient, this process seems
to be completely suppressed. It has been suggested that
enhanced stability of active substances in binary systems with
acetylated maltose and sucrose is most likely due to
additional barriers related to (a) intermolecular interactions
and/or (b) diffusion of API in the saccharide matrix that must
be overcome to trigger the crystallization process. In
formulations comprising a saccharide matrix, the API remained
stable even after 1 year of storage at room temperature.
These results are excellent prerequisite for a formulation
study. Thus, it was decided to check whether the GSDFs
obtained by co-melting nifedipine and acetylated sucrose
investigated in this study are robust with respect to the
exposure to media of different pH as well as mechanical stress
of biorelevant intensity.
Dissolution/Release from Surface
The use of active substances molten/mixed with modified
saccharides offers the additional advantage of flexible
adjustment of the drug delivery rate in order to meet the
therapeutic requirements. During the dissolution tests
performed using different setups and dissolution media as well as
incubation in solutions of colorants and digestive enzymes, it
was observed that the dissolution of nifedipine from GSDFs
Fig. 2. Results of solubility study of crystalline form of nifedipine (a)
and amorphous solid dispersion of nifedipine with acetylated sucrose
(b). Given are means of n = 3; the standard deviation is given by error
takes place only from the surface of the melts (Figs. 1b and
6). The dissolution characteristics of the GSFDs were
independent on the type and concentration of the used
surfactants (Fig. 5). Therefore, it is likely that dissolution
rate of GSDF compositions can be easily adjusted by
changing the contact surface area of the binary glassy systems
to the dissolution medium by simple means of size and shape
Furthermore, modifications of the dissolution
characteristics can be achieved by varying the drug load in the solid
n.a. not available; USP - United States Pharmacopeia
Regression coefficients R2
Fig. 5. Dissolution of GSDFs with nifedipine in the stress test device
under 19+1 stress sequence using USP phosphate buffer pH 6.8 with
0.1, 0.5 and 1.0%SLS as well as FeSSIF dissolution medium. Given
are means of n = 3; standard deviation is indicated by the error bars
dispersion as well as by adjustment of the solubility kinetics of
octaacetyl sucrose using alternative excipients. These
modifications could be achieved by using other acetylated
saccharides, such as acetylated maltose for which the stabilizing
effect towards amorphous drug substances has been already
). This will allow for a well-definable and
controlled release of the drug, proceeding independently of
physiological conditions of the human gastro intestinal
Protection Against Recrystallization
One of the critical factors limiting the use of amorphous
drugs is the hydration of the dosage form. It has been
recognized that exposition to moisture or significant humidity
levels, prior to dissolution of the API from the dosage form,
can trigger recrystallization of amorphous APIs (
Recrystallization not only changes the solubility and
dissolution rate but may also alter the delivery kinetics of the dosage
form as a whole. Nonetheless, all currently known MR
systems require water to be available for polymer swelling
or building up osmotic pressure (28).
In the case of ionizable drugs, it may implicate solubility
issues which can be at least partially overcome by buffering of
the MR matrices or reducing the exposition time by
controlling the water penetration into the tablet core during
). However, with currently available MR
systems, the exposition of the drugs to water prior to their
release cannot be avoided.
This major challenge can be overcome by the use of
nonhydrating systems that facilitate the incorporation of the
drugs in molecular dispersions or suspensions. Most desirable
matrices should be of low porosity and exhibit very limited
and slow water uptake and swelling. Moreover, a
dissolution profile should be independent of the pH and composition
of the GI fluids. Thus, such delivery systems would release
the active substance only from their surfaces exposed to the
GI fluids. Thereby, the exposition time of the drug compound
to the aqueous media prior to dissolution would be
minimized. Consequently, such systems would bring about
advantageous stabilization of the amorphous form of API. So far, a
large number of polymeric materials of different water affinity
and solubilization behavior is available, including
p o l y v i n y l p y r o l i d o n e ( e . g . , K o l l i d o n ) o r p o l y v i n y l
caprolactam-polyvinyl acetate-polyethylene glycol graft
copolymer (e.g., Soluplus) and others that could be useful for
this purpose (
). However, these commonly applied
pharmaceutical excipients still bear a risk of water uptake and
exposure of the drug substances to the GI liquids prior to
Interestingly, the advantageous drug delivery systems
characterized by limited or no water sorption during drug
delivery can be manufactured using a variety of thermoplastic
unit operations, such as melt extrusion, 3D print, or other
melt-based technologies using thermostable excipients of
desired properties. Owing to their properties saccharides,
especially modified ones, seems to be quite an interesting
alternative for manufacturing novel dosage forms for
controlled delivery of the amorphous forms of poorly water
Comparison with Commercial ER Systems—Potential
Consequences for Pharmacokinetics
Dissolution profiles obtained under standard and stress
conditions were compared with two different types of
commercially available MR formulation containing
nifedipine. One was a conventional MR tablet—matrix system, of
which the drug release is erosion controlled and the other
being an osmotic push pull system (OROS).
The pharmacokinetic (PK) properties of one of the
OROS systems have been investigated previously under
fasted and fed conditions by Schug et al. and Wonnemann
et al. The PK profiles obtained for OROS have been reported
to be smooth and indicated the absence of sharp plasma
peaks or dose dumping events. A lag time of 2 to 3 h has been
observed for this drug product (
). This seems to be a
distinct characteristic of the OROS formulation. From the
biopharmaceutical point of view, such characteristics are very
important, especially under fed conditions, when released
drug substance can accumulate in the stomach for some time
as described by Weitchies et al. (31,32). As reported, the
accumulation of released API in the stomach is independent
of the dosage form delivery characteristics and occurs mainly
in the proximal stomach. In this part of the stomach, tablets
may reside for several hours after intake. Due to intragastric
mixing and gastric emptying patterns, a large portion of a
drug substance that accumulated in the stomach can be
transferred into the intestine, thereby causing unexpected,
elevated drug plasma levels. According to Weitschies et al.
(32), the positive food effects can be related to the intragastric
localization and absence of the lag time in the dissolution
characteristic of a MR formulation. Such undesired drug
delivery behavior has been observed for modified release
tablets containing felodipine. However, in the reported case,
elevated drug plasma levels have been related to the
physiology of gastric emptying, not to the dissolution
characteristics of the dosage form itself (31).
Opposed to the OROS, the onset of nifedipine
dissolution in vitro from the novel GSDFs appeared immediately
after immersion into the dissolution media. Nevertheless, the
GSDFs as presented herein could easily be coated with a
time-dependent coating to achieve a similar lag time to the
The GSDFs are monolithic drug delivery systems and the
high variability of gastric emptying times, depending on the
prandial conditions as well as food intake, could oppose
achievement of the desired release profile. However, owing to
the properties of the GSDFs containing octaacetyl sucrose
and nifedipine in conjunction with the flexibility of the
formulation parameters, this challenge could be met by
manufacturing multiparticulate delivery systems. The release
profile could then be controlled by adaption of the size and
shape of the GSFDs.
Details regarding the pharmacokinetic profiles of the MR
tablet formulation included in this study have been reported
elsewhere (30). It has been found that in fasted subjects, the
maximum nifedipine plasma concentrations were higher after
administration of MR tablets than after intake of the OROS
formulation. Administration postprandial to a high caloric
food—high fat, american breakfast—have yielded an even more
profound difference. Up to a threefold increase of the mean
Cmax has been observed under such conditions in comparison to
fasted subjects. On the other hand, food intake has been shown
to have no clinically relevant effect on the bioavailability of
nifedipine delivered by the OROS GITS. Wonneman et al. have
postulated that the observed differences between these two
products may have direct therapeutic relevance when
substituting a given formulation by the other one (30). This should be
particularly taken into consideration if administration
conditions are changed in conjunction to the formulation (e.g., fasted
to fed-state administration) since the pharmacological and
therapeutic actions are closely associated to the drug plasma
Besides the abovementioned food effects, it has been
found that the dissolution profiles of the MR tablets can be
also influenced by the pH as well as mechanical stress of
biorelevant intensity. These dissolution characteristics of MR
tablets have been reported to bear the potential risk of
unwanted drug delivery behavior in vivo. The
pharmacokinetic and dissolution characteristics of products having an
analogous galenic composition have been previously
). In contrast, the dissolution of nifedipine from
GSDFs was not affected by the pH of the medium, the type of
surfactants and their concentration, or the simulated
mechanical stress. In this context, it could be expected that the
developed GSDF dosage form would have more reliable
in vivo performance (closer to OROS than to matrix tablets).
This provides an excellent opportunity to design solid oral
dosage forms having stable and predictable nifedipine (and
other BCS class II drugs) delivery kinetics in vivo.
Previously performed, the pre-formulation studies have
proven that modified saccharides such as acetylated sucrose
can stabilize the amorphous form of BCS class II drug
substances. Based on these findings, amorphous nifedipine
solid dispersion with octaacetyl sucrose (GSDFs) were
developed. The presented work demonstrated that the use
of amorphous binary mixture containing the model, poorly
soluble API, nifedipine, and octaacetyl sucrose can be used
for preparation of novel oral MR systems. The drug delivery
from the novel dosage forms was independent on the
dissolution medium pH and mechanical agitation as well as
concentration and type of the added surfactants. The
performance of the novel formulation was comparable to
the Adalat OROS GITS. However, the manufacturing
technology is potentially simpler, robust, reproducible, and
easier than in the case of OROS formulations. The novel
glassy melt formulation protects amorphous nifedipine from
contact with water and subsequent recrystallization. Low
variability of the dissolution characteristics as well as
independence on pH and simulated gastric stress are good
prerequisites for well-definable drug kinetics in vivo.
EK is thankful for the financial support from the
National Science Center of Poland based on decision No.
DEC-2016/22/E/NZ7/00266. DHG and GG kindly
acknowledge the financial support of the German General Federal
Ministry of Education and Research (BMBF 03IPT612C).
Open Access This article is distributed under the terms
of the Creative Commons Attribution 4.0 International
License (http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction in
any medium, provided you give appropriate credit to the
original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were
1. Kasim NA , Whitehouse M , Ramachandran C , Bermejo M , Lennernäs H , Hussain AS , et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification . Mol Pharm . 2004 ; 1 ( 1 ): 85 - 96 . https://doi.org/10.1021/mp034006h.
2. Miyaji Y , Fujii Y , Takeyama S , Kawai Y , Kataoka M , Takahashi M , et al. Advantage of the dissolution/permeation system for estimating oral absorption of drug candidates in the drug discovery stage . Mol Pharm . 2016 ; 13 ( 5 ): 1564 - 74 . https:// doi.org/10.1021/acs.molpharmaceut.6b00044.
3. Kumar A , Sahoo SK , Padhee K , Kochar P , Satapathy A , Pathak N. Review on solubility enhancement techniques for hydrophobic drugs . Pharmacie Globale . 2011 ; 3 ( 3 ): 001 - 7 .
4. Yu L . Amorphous pharmaceutical solids: preparation, characterization and stabilization . Adv Drug Deliv Rev . 2001 ; 48 ( 1 ): 27 - 42 . https://doi.org/10.1016/ S0169 -409X( 01 ) 00098 - 9 .
5. Kaminski K , Kaminska E , Adrjanowicz K , Grzybowiska K , Wlodarczyk P , Paluch M , et al. Dielectric relaxation study on tramadol monohydrate and its hydrochloride salt . J Pharm Sci . 2010 ; 99 ( 1 ): 94 - 106 . https://doi.org/10.1002/jps.21799.
6. Kaminska E , Adrjanowicz K , Kaminski K , Wlodarczyk P , Hawelek L , Kolodziejczyk K , et al. A new way of stabilization of furosemide upon cryogenic grinding by using acylated saccharides matrices. The role of hydrogen bonds in decomposition mechanism . Mol Pharm . 2013 ; 10 ( 5 ): 1824 - 35 .
7. Boldyrev VV . Mechanochemical modification and synthesis of drugs . J Mater Sci . 2004 ; 39 ( 16 ): 5117 - 20 . https://doi.org/10.1023/ B:JMSC. 0000039193 .69784. 1d .
8. Einfal T , Planinsek O , Hrovat K. Methods of amorphization and investigation of the amorphous state . Acta Pharmaceutica (Zagreb, Croatia). 2013 ; 63 ( 3 ): 305 - 34 . https://doi.org/10.2478/ acph-2013-0026.
9. Dawson KJ , Kearns KL , Yu L , Steffen W , Ediger MD . Physical vapor deposition as a route to hidden amorphous states . Proc Natl Acad Sci U S A . 2009 ; 106 ( 36 ): 15165 - 70 . https://doi.org/ 10.1073/pnas.0901469106.
10. Yadav VB , Yadav AV . Enhancement of solubility and dissolution rate of BCS class II pharmaceuticals by nonaquious granulation technique . Int J Pharm Res Devel . 2010 ; 12 : 1 - 12 .
11. Adrjanowicz K , Grzybowska K , Kaminski K , Hawelek L , Paluch M , Zakowiecki D. Comprehensive studies on physical and chemical stability in liquid and glassy states of telmisartan (TEL): solubility advantages given by cryomilled and quenched material . Philos Mag . 2011 ; 91 ( 13 -15): 1926 - 48 . https://doi.org/ 10.1080/14786435. 2010 . 534742 .
12. Craig DQ , Royall PG , Kett VL , Hopton ML . The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems . Int J Pharm . 1999 ; 179 ( 2 ): 179 - 207 .
13. Qi S , Weuts I , De Cort S , Stokbroekx S , Leemans R , Reading M , et al. An investigation into the crystallisation behaviour of an amorphous cryomilled pharmaceutical material above and below the glass transition temperature . J Pharm Sci . 2010 ; 99 ( 1 ): 196 - 208 . https://doi.org/10.1002/jps.21811.
14. Gupta P , Thilagavathi R , Chakraborti AK , Bansal AK . Role of molecular interaction in stability of celecoxib-PVP amorphous systems . Mol Pharm . 2005 ; 2 ( 5 ): 384 - 91 . https://doi.org/10.1021/ mp050004g.
15. Tobyn M , Brown J , Dennis AB , Fakes M , Gao Q , Gamble J , et al. Amorphous drug-PVP dispersions: application of theoretical, thermal and spectroscopic analytical techniques to the study of a molecule with intermolecular bonds in both the crystalline and pure amorphous state . J Pharm Sci . 2009 ; 98 ( 9 ): 3456 - 68 . https://doi.org/10.1002/jps.21738.
16. Wegiel LA , Mauer LJ , Edgar KJ , Taylor LS . Crystallization of amorphous solid dispersions of resveratrol during preparation and storage-impact of different polymers . J Pharm Sci . 2013 ; 102 ( 1 ): 171 - 84 . https://doi.org/10.1002/jps.23358.
17. Kaminska E , Adrjanowicz K , Tarnacka M , Kolodziejczyk K , Dulski M , Mapesa EU , et al. Impact of inter- and intramolecular interactions on the physical stability of indomethacin dispersed in acetylated saccharides . Mol Pharm . 2014 ; 11 ( 8 ): 2935 - 47 . https://doi.org/10.1021/mp500286b.
18. Kaminska E , Tarnacka M , Kolodziejczyk K , Dulski M , Zakowiecki D , Hawelek L , et al. Impact of low molecular weight excipient octaacetylmaltose on the liquid crystalline ordering and molecular dynamics in the supercooled liquid and glassy state of itraconazole . Eur J Pharm Biopharm: Off J Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e V. 2 0 1 4 ; 8 8 ( 3 ) : 1 0 9 4 - 1 0 4 . h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j.ejpb. 2014 . 10 .002.
19. Toal CB . Formulation dependent pharmacokinetics-does the dosage form matter for Nifedipine? J Cardiovasc Pharmacol . 2004 ; 44 ( 1 ): 82 - 6 .
20. Walley TJ , Heagerty AM , Woods KL , Bing RF , Pohl JE , Barnett DB . Pharmacokinetics and pharmacodynamics of nifedipine infusion in normal volunteers . Br J Clin Pharmacol. 1 9 8 7 ; 2 3 ( 6 ) : 6 9 3 - 7 0 1 . h t t p s : / / d o i . o r g / 1 0 . 1111 / j . 1 3 6 5 - 2125 . 1987 .tb03103.x.
21. Soons PA , Schoemaker HC , Cohen AF , Breimer DD . Intraindividual variability in nifedipine pharmacokinetics and effects in healthy subjects . J Clin Pharmacol . 1992 ; 32 ( 4 ): 324 - 31 . https://doi.org/10.1002/j.1552- 4604 . 1992 .tb03843.x.
22. Kaminska E , Tarnacka M , Wlodarczyk P , Jurkiewicz K , Kolodziejczyk K , Dulski M , et al. Studying the impact of modified saccharides on the molecular dynamics and crystallization tendencies of model API nifedipine . Mol Pharm. 2 0 1 5 ; 1 2 ( 8 ) : 3 0 0 7 - 1 9 . h t t p s : / / d o i . o r g / 1 0 . 1 0 2 1 / acs.molpharmaceut.5b00271.
23. Qian F , Huang J , Hussain MA . Drug-polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development . J Pharm Sci . 2010 ; 99 ( 7 ): 2941 - 7 . https://doi.org/10.1002/jps.22074.
24. Garbacz G , Wedemeyer RS , Nagel S , Giessmann T , Monnikes H , Wilson CG , et al. Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses . Eur J Pharm Biopharm: Off J Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV . 2008 ; 70 ( 2 ): 421 - 8 .
25. Daniel Bar-Shalom KN , Clive Wilson. An evaluation of the roles of erodible systems in the oral drug delivery toolbox: the importance of geometry in therapeutic delivery tablets & capsules . 2012; September: 32 - 9 .
26. Colombo P , Bettini R , Peppas NA . Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug . J Control Release . 1999 ; 61 ( 1-2 ): 83 - 91 . https://doi.org/ 10.1016/S0168- 3659 ( 99 ) 00104 - 2 .
27. Colombo P , Bettini R , Santi P , Peppas NA . Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance . Pharm Sci Technol Today . 2000 ; 3 ( 6 ): 198 - 204 . https://doi.org/10.1016/S1461- 5347 ( 00 ) 00269 - 8 .
28. Al-Taani BM , Tashtoush BM . Effect of microenvironment pH of swellable and erodable buffered matrices on the release characteristics of diclofenac sodium . AAPS PharmSciTech . 2003 ; 4 ( 3 ): 110 - 5 . https://doi.org/10.1208/pt040343.
29. Schug BS , Brendel E , Wolf D , Wonnemann M , Wargenau M , Blume HH . Formulation-dependent food effects demonstrated for nifedipine modified-release preparations marketed in the European Union . Eur J Pharm Sci: Off J Eur Fed Pharm Sci.
Wonnemann M , Schug B , Schmucker K , Brendel E , van Zwieten PA , Blume H . Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union . Int J Clin Pharmacol Ther . 2006 ; 44 ( 1 ): 38 - 48 .
Weitschies W , Friedrich C , Wedemeyer RS , Schmidtmann M , Kosch O , Kinzig M , et al. Bioavailability of amoxicillin and clavulanic acid from extended release tablets depends on intragastric tablet deposition and gastric emptying . Eur J Pharm Biopharm: Off J Arbeitsgemeinschaft fur Pharmazeutische 32 .
Verfahrenstechnik eV . 2008 ; 70 ( 2 ): 641 - 8 . https://doi.org/10.1016/ j.ejpb. 2008 . 05 .011.
Weitschies W , Wedemeyer R-S , Kosch O , Fach K , Nagel S , Söderlind E , et al. Impact of the intragastric location of extended release tablets on food interactions . J Control Release . 2005 ; 108 ( 2-3 ): 375 - 85 . https://doi.org/10.1016/ j.jconrel. 2005 . 08 .018.
Garbacz G , Blume H , Weitschies W. Investigation of the dissolution characteristics of nifedipine extended-release formulations using USP apparatus 2 and a novel dissolution apparatus . Dissolut Technol . 2009 ; 16 : 7 - 13 .