Maninder Karan et al. / Journal of Pharmacy Research 2012,5(4),2022-2026
Research Article
ISSN: 0974-6943
Available online through
http://jprsolutions.info
Cocrystal of caffeine with propionic acid: Preliminary characterization and stability evaluation
Maninder Karan 1* , Kunal Chadha 1, Renu Chadha 1 and Anupam Saini 1
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, INDIA.
*Dr. Maninder Karan, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, INDIA.
Received on:04-01-2012; Revised on: 17-02-2012; Accepted on:20-03-2012
ABSTRACT
Caffeine, a central nervous system stimulant, exhibits reversible crystalline hydrate formation that complicates the design of a reproducible formulation
in drug devepoment process. Thus, the goal of the current study is to prepare cocrystal of caffeine that exhibits enhanced physical stability as a function
of relative humidity. The solution based cocrystallization experiment on caffeine and propionic acid resulted in a molecular complex that was characterized by thermal and spectroscopic techniques. The DSC and TGA results suggested formation of cocrystal of caffeine with propionic acid in 1:1
stoichiometry. The appearance of few new peaks in XRPD pattern confirmed the formation of new crystalline phase. Based upon shifts observed in IR
bands of caffeine and propionic acid in FT-IR spectrum of cocrystal, intermolecular hydrogen bond interactions, O-H···N and C-H···O are predicted
between this drug and coformer. The molar enthalpy of solution (∆Hsol) was determined for drug, coformer and their cocrystal. The latter was found to be
more endothermic than the expected ∆Hsol of physical mixture calculated on the basis of individual values of the starting components. Further, this
cocrystal exhibited solid state stability at 43 % RH over a period of 4 weeks, but, was found to be unstable under higher RH conditions.
Key words: Caffeine, cocrystal, coformer, propionic acid, stability.
INTRODUCTION
Solid dosage forms of active pharmaceutical ingredients (APIs) often face
the problem of poor solubility or stability during drug development process. Thus, to achieve optimum performance of drug formulations, manipulations of the API solid form is sometimes desirable. In doing so, the formulation scientists turn to various methods, like salt1, polymorph2,3, solvate4,5, cocrystal6 or amorphous7 formation. Although the formation of salts
is an excellent means of altering the physicochemical properties of an API,
this method suffers from the inherent drawback that it requires at least one
ionizable center on the API8. Furthermore, the number of pharmaceutically
acceptable salt formers is relatively small9. On the other hand, solid-state
manipulations can increase the risk of phase conversion under normal storage conditions10,11.
During this decade, cocrystallization approach has been gaining widespread
attention in pharmaceutical industry as a means of tailoring the physicochemical properties such as solubility12, bioavailability13, melting point14,15
or physical stability16,17 of an API. Pharmaceutical cocrystal is defined as a
crystalline molecular complex in which individual neutral molecules of an
API and a pharmaceutically acceptable coformer are held together by noncovalent interactions, most often, the hydrogen bonds18.
The API under consideration in the current report is caffeine, a well known
central nervous system stimulant and a smooth muscle relaxant19. It is
known to exist as two anhydrous crystal forms (a, ß) with the stable
anhydrous ß-caffeine crystal form converting to the metastable a-caffeine
at high temperature20. Unfortunately, crystalline powder of both the anhydrous a- and ß-caffeine exhibits instability with respect to humidity and
converts to a crystalline non-stoichiometric hydrate at high relative humidity21. Thus, stability in the presence of atmospheric moisture, is a major
*Corresponding author.
Maninder Karan
University Institute of Pharmaceutical
Sciences, Panjab University,
Chandigarh-160014, India
concern in the development of caffeine. Cocrystallization of caffeine with
some suitable carboxylic acids of GRAS (generally regarded as safe) status
such as oxalic acid, malonic acid, maleic acid, glutaric acid16, formic acid,
acetic acid and trifluoroacetic acid22 have been found to be useful for pre
venting the incorporation of lattice water into caffeine cocrystal. The present
study reports another cocrystal of caffeine (CAF) with propionic acid
(PA), a coformer of GRAS status23. Characterization was done by utilizing
differential scanning calorimetry (DSC)/ thermogravimetric analysis (TGA),
X-ray powder diffraction (XRPD) and Fourier-transform infra-red (FT-IR)
spectroscopy. Further, stability studies were performed on this cocrystal
under varying relative humidity (RH) conditions and it was found to exhibit
enhanced physical stability as compared to pure anhydrous caffeine under
lower RH conditions.
MATERIALS AND METHODS
Materials
Caffeine anhydrous and Propionic acid (99% purity) were purchased from
S. D. Fine Chem. Ltd, Mumbai and were used as received.
Sample Preparation
The cocrystal CAF-PA was prepared by solution crystallization method.
Anhydrous caffeine was added to a large excess of propionic acid with heat
and the clear solution obtained was allowed to evaporate slowly under
ambient conditions. Needle shaped crystals appeared within few hours that
were filtered, air dried and stored properly in tightly closed vials.
Differential Scanning Calorimetry (DSC)
Differential scanning calorimetry of CAF-PA as well as the starting material
was conducted using DSC Q20 (TA Instruments, USA). The samples (3-5
mg) were placed in sealed non-hermetic aluminium pans and were scanned
at a ramping rate of 10 °C/min under a dry nitrogen atmosphere (flow rate
50 mL/min).
Thermogravimetric Analysis (TGA)
TGA was performed on a Mettler Toledo TGA/SDTA 851e instrument.
Approximately 5 mg sample was heated from 10 to 250 °C in open alumina
pan at the rate of 10 °C/min under nitrogen purge at flow rate of 50 mL/min.
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X-ray Powder Diffraction (XRPD)
XRPD patterns were collected on X’Pert PRO diffractometer system
(Panalytical, Netherlands) with a Cu Ka radiation (1.54060 Ar). The tube
voltage and current were set at 45 kV and 40 mA respectively. The divergence slit and anti-scattering slit settings were set at 0.48° for the illumination on the 10 mm sample size. Each sample was packed in an aluminium
sample holder and measured by a continuous scan between 5° and 50° in 2?
with a step size of 0.017°.
Fourier Transform-Infra Red Spectroscopy (FT-IR)
A Spectrum RX I FT-IR spectrometer (Perkin Elmer, UK) was employed
in the KBr diffuse-reflectance mode (sample concentration 2 mg in 20 mg of
KBr) for collecting the IR spectra of samples. The spectra were measured
over the range of 4000-400 cm-1.
Solution Calorimetric Study
Calorimetric studies were performed on microreaction calorimeter obtained
from Thermal Hazards Technology, UK. Phosphate buffer (pH 7) was
used to determine the enthalpy of solution and the measurements were
performed at 37 °C. The size of sample used in this study ranged from 1 to
10 mg and was weighed (Sartorius Model CP225D) into a cylindrical glass
tube covered with paraffin film on one side. This cylindrical tube was
submerged into the ampoule containing the solvent. A plunger with a cap
was put from the open end of the tube. The same solvent was put into the
reference ampoule. These were put into the sample and reference holes
until both rests on the base of the holes. The apparatus was maintained at
constant temperature at 37 °C (± 0.0005 °C). The paraffin film was shattered mechanically by means of plunger. In the case of liquid sample
(propionic acid), the enthalpy of solution in buffer was determined using
the titration mode of the Micro Reaction Calorimeter. The reference and
sample vials filled with equal volume of buffer were placed in a calorimetric
block set at 37 °C. A 100 µl syringe loaded with propionic acid was mounted
on the sample vial. After baseline stabilization, 50 µl of the acid was injected into the sample vial and the heat output recorded and integrated to
calculate the enthalpy of solution.
Equilibrium Solubility Studies
Equilibrium solubility studies of caffeine and its cocrystals were performed
by introducing excess amount of samples in water which were shaken in
water bath shaker (MSW-275 Macroscientific works, Delhi) at 25 °C. The
aliquots were withdrawn from the slurry after 24 hours, filtered through a
0.45 µm membrane filter (Millipore), diluted suitably and concentration
determined by measuring the absorption at λmax of caffeine (272.4 nm) using
Perkin Elmer, Lambda 25, UV/VIS spectrophotometer.
Stability Studies
To compare the stability of anhydrous caffeine to that of its cocrystal
CAF-PA, samples of both were evaluated for physical stability at conditions of 0, 43, 75 and 98 % RH for time periods of 1, 3, 7 and 30 days.
Relative humidity conditions at 25 °C were achieved within sealed glass
desiccator jars containing P 2O5 for the 0 % RH condition and appropriate
saturated aqueous salt solutions for other RH values; K2CO3 for 43 %;
NaCl for 75 %; K2SO4 for 98 %24. Relative humidity conditions were monitored using humidity indicator cards. Open glass vials containing 300-400
mg of pure anhydrous caffeine as well as cocrystal were stored in the RH
chamber at a temperature of 25 °C. A vial was removed for each sample at
each time point. Upon removal from the chamber, the samples were
promptly evaluated for any form change by XRPD and FT-IR to provide
an insight into their stability.
Table 1: Enthalpy of solution of drug, coformer, their physical mixture and cocrystal.
Sample
Amount
(mg)
Caffeine
1.54
Propionic acid
99
(Density = 0.99 g/mL)
CAF:PA (1:1 Physical mixture) CAF-PA Cocrystal
2.95
Concentration
(M)
Enthalpy of solution
(kJ/mol)
7.9 ×10-6
1.09×10-3
2.71
-1.26
10.9×10-6
1.44 (calculated theoretically)
10.9
Table 2: Solubility of caffeine and its cocrystals after slurrying in water for 24 h at 25 °C.
Compound
Concentration achieved
after slurrying in water
for 24 hrs (mg/ml)
pH
Conversion to caffeine hydrate
â-caffeine
3.21
4.83
Yes
CAF-PA cocrystal 9.32
3.17
Yes
Table 3: Stability studies of caffeine and its cocrystal with respect to RH.
Material
Condition Observed relative humidity (RH) stability after *
(% RH)
1 day
3 days 1 week
4 weeks
Caffeine
0
43
75
98
0
43
75
98
CAF-PA
v
v
×
×
v
v
v
×
v
×
×
×
v
v
v
×
v
×
×
×
v
v
×
×
v
×
×
×
v
v
×
×
* Note: The symbol v indicates that the crystalline material was stable at that condition and time
point. The symbol × indicated that the crystalline material exhibited physical instability at that
time point.
O
N
N
O
O
N
N
C a ff e in e
OH
P ro p io n ic a c id
Scheme 1. Molecular structures of caffeine and propionic acid.
Scheme 2. Heteromeric synthon showing O-H···N and C-H···O hydrogen bond interactions
proposed between propionic acid and caffeine.
RESULTS AND DISCUSSION
The coformer used in this study is a liquid at ambient temperature, justifying the term ‘solvate’ as an alternative to ‘cocrystal’ as a descriptor of the
crystalline complex reported here. However, the solvate formation has
been an unplanned outcome of a crystallization, whereas cocrystal formation is gaining precedence as a premeditated strategy by which one may
Scheme 3. Hydrogen bonding patterns expected in CAF-PA cocrystal.
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Figure 1. DSC scans of (a) Commercial sample of ß-caffeine, (b) caffeine-propionic acid
cocrystal; CAF-PA.
Figure 4. FT-IR spectrum of (a) ß-caffeine, (b) propionic acid, (c) caffeine-propionic acid
cocrystal; CAF-PA, (d) solid residues obtained after slurrying of caffeine in water (e) solid
residues obtained after slurrying of CAF-PA in water for 24 hrs.
surmount physicochemical property challenges of APIs22. Therefore, the
latter description best fits the results presented herein. The molecular structures of caffeine and propionic acid are represented in scheme 1.
Figure 2. TGA scans of (a) Commercial sample of ß-caffeine, (b) caffeine-propionic acid
cocrystal; CAF-PA.
Figure 3. XRPD patterns of (a) ß-caffeine, (b) CAF-PA cocrystal, (c) solid residues obtained
after slurrying of caffeine in water (d) solid residues obtained after slurrying of CAF-PA in
water.
Differential scanning calorimetry (DSC) and thermogravimetric
analysis (TGA)
DSC analysis has been shown to be a very powerful analytical technique in
the characterization of the solid-state interactions between drug and
coformers through the appearance, shift or disappearance of endothermal
or exothermal effects and/or variations in the relevant enthalpy. Anhydrous
caffeine has been reported to exist in two different polymorphic forms (α
and ß). Therefore, the available commercial sample was characterized first
to confirm its identity by DSC and TGA. The DSC thermogram (Fig. 1) of
caffeine showed a small broad endotherm at 150.23 °C followed by a sharp
melting peak at 235.48 °C revealing the transformation of ß-caffeine upon
heating at temperature above 150 °C through a transition to a-caffeine
which finally melted at 237 °C. This correlated well with that reported by
Susana S Pinto25. The TGA scan (Fig. 2) of this commercial sample did not
show any weight loss confirming that the small endotherm at 150 °C in
DSC was not due to any desolvation, but because of some phase transition.
It also confirmed the commercial sample used in the present study to be
anhydrous ß-caffeine.
In DSC scan of CAF-PA (Fig. 1), four major events were observed. The
first sharp endothermic peak at 69.32 °C is associated with a weight loss of
25.3 % in TGA which indicated the melting of cocrystal with simultaneous
release of propionic acid from the crystal lattice. The weight loss in TGA
(Fig. 2) correlated well with theoretical weight loss of 27.6 % corresponding to a single molecule of propionic acid suggesting a stoichiometry of 1:1
between caffeine and propionic acid. This broad peak in DSC was immediately followed by a small exotherm suggesting the recrystallization of caffeine to its ß form. This exotherm was succeeded by a small endothermic
transition at 148.80 °C which revealed the phase transformation of the
recrystallized ß-caffeine to its a-form that subsequently melted at 237.21
°C. All these thermal events in DSC together with TGA results suggested
that CAF-PA was a multicomponent crystal of ß-caffeine and propionic
acid with 1:1 stoichiometry.
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X- Ray Powder Diffraction (XRPD)
Powder XRD is a useful method for fast identification of the new phases.
CAF-PA exhibited unique crystalline XRPD pattern in comparison to pure
caffeine indicating the generation of a new solid phase. The XRPD pattern
of caffeine (Fig. 3) showed peaks at 8.32°, 11.79°, 12.00°, 14.45°, 15.74°,
19.69°, 20.57°, 24.04°, 25.98°, 26.42°, 27.03° and 28.36° while the cocrystal
CAF-PA (Fig. 3) showed characteristic peaks at 7.01°, 9.58°, 9.71°, 13.70°,
13.88°, 17.79°, 17.96°, 19.12°, 19.39°, 20.63°, 20.79°, 26.69° and 28.50°.
Thus, the XRPD pattern of CAF-PA showed many unique peaks which
were absent in the XRPD pattern of caffeine. In addition, the intensity of
peaks in the XRPD pattern of CAF-PA cocrystal increased indicating that
the newer form obtained was more crystalline than commercial sample of
caffeine.
Although the formation of new solid phases in both the cocrystals have
been identified by DSC/ TGA and XRPD analysis, however, the evidence
of hydrogen bonding interactions was obtained by FT-IR spectroscopy
and solution calorimetry studies.
Fourier Transform Infrared Spectroscopy (FT-IR)
The FT-IR spectra of caffeine, propionic acid and CAF-PA are presented in
Fig. 4. Caffeine showed characteristic secondary amine N-H stretch at
3109.1 cm-1, an alkyl -C-H stretch at 2952.6 cm-1, amide -C=O stretch at
1702.2 cm-1, -C=N- stretch at 1655.5 cm-1 and =C–H out-of-plane bands at
970.3 and 862.4 cm-1. All these bands appeared in the FT-IR spectra of
CAF-PA but with shifts in the frequencies of -C=N- stretch and in =C–H
out-of-plane bands which appeared at 1664.2 cm-1 and 981.8 & 855.7 cm-1
respectively. These shifts suggested that both the N atom of -C=N- and H
atom of = C–H group of caffeine were involved in some kind of hydrogen
bond interactions. Similarly, the C=O stretch of propionic acid at 1717.4
cm-1 also shifted to 1735.4 cm-1 in CAF-PA suggesting that both the N of
-C=N- group of caffeine and -C=O of COOH group of propionic acid
participated in hydrogen bond formation. Besides this, the appearance of
two additional bonds at 2450 and 1950 cm-1 were observed in FTIR spectra
of CAF-PA, further confirming a hydrogen bonding between the drug and
the coformer. This explanation is based upon the observation made by
Aakeroy et al26 that if a neutral intermolecular O-H...N hydrogen bond is
formed between a carboxylic acid and a base, then two broad stretches
around 2450 and 1950 cm-1 provide a clear evidence of cocrystal formation.
The appearance of two such broad bands was clearly observed in the FTIR
spectrum of CAF-PA, thus, confirming the hydrogen bonding between
caffeine and propionic acid in CAF-PA. FTIR studies thus provided a clear
evidence of cocrystal formation between caffeine and propionic acid.
Solution Calorimetry
Solution calorimetry is a thermal technique which monitors the heat of
solution at constant temperature. It allows the direct measurement of heat
change caused by dissolution of solid phase into a particular media27. Calorimetrically determined enthalpy of solution which depends upon the lattice energy and crystal structure has great potential in characterization of
cocrystals. In cocrystals, complementary functional groups of two different molecules result in specific hydrogen bonding that is energetically more
favourable than that between like molecules of either component. Thus, the
cocrystals are thermodynamically favoured.
The enthalpy of solution of individual components (drug and coformers)
and cocrystal was determined in phosphate buffer pH 7.0. Molar enthalpy
of solution for physical mixture of starting components was also calculated
theoretically according to equation (1).
∆Hsol (CAL) = 0.5 × (∆HD) + 0.5 × (∆HCCF)…………………………… (1)
∆Hsol (CAL) = Calculated molar enthalpy of solution of physical mixture
∆Hsol (D) = Molar enthalpy of solution of drug
∆Hsol (CCF) = Molar enthalpy of solution of cocrystal former
It is evident from the Table 1 that caffeine, propionic acid and the cocrystal
CAF-PA showed endothermic behaviour. However, the molar enthalpy of
solution for cocrystal was found to be more endothermic than the experimental and theoretically calculated molar enthalpy of solution of physical
mixture of drug and coformer. This may be explained by the fact that in
solution phase, breaking of the hydrogen bonds (an endothermic process) is
responsible for the increment in the endothermic effect of cocrystal. The
excess enthalpy of the solution which is the measure of hydrogen bond
between components gives an idea that cocrystals are sustained by strong
hydrogen bonds.
The expected cocrystal design for CAF-PA was rationally based on a known
acid-base supramolecular synthon and the intermolecular hydrogen bonding pattern is shown in scheme 2. The hydrogen bonds were expected
between caffeine and acid molecules. The carboxyl acid moiety of propionic acid formed an O-H…..N hydrogen bond with the imidazole nitrogen
atom of caffeine, while the other self-complementary C-H….O hydrogen
bond was expected from imidazole of caffeine to carbonyl of acid molecule
in CAF-PA. This hydrogen bonding arrangement suggested a 1:1 stoichiometry in the resultant cocrystal.
Solubility Studies
Slurry experiment was performed on caffeine and its cocrystal CAF-PA in
water at 25 °C for 24 h and the concentration of caffeine was determined in
each sample after 24 h. The absorptivity (ε) of caffeine in water was measured to be 52 mL mg-1 cm-1 at 272.4 nm and this value was used to calculate
the concentration of solutions of slurry experiments. The pH of each sample
after 24 h was also noted and is given in Table 2. The concentration of
caffeine was higher in cocrystal as compared to pure caffeine. Since caffeine
is a basic compound, it is reported to exhibit pH dependent solubility
(increase in solubility with decrease in pH). This explains the increased
solubility of cocrystal which is attributed to decrease in pH of the medium
due to release of propionic acid upon dissolution of cocrystal. However,
the absolute value of solubility of caffeine was still lesser as compared to
literature value (21.7 mg/mL)28. This has been well explained by the XRPD
and FT-IR analysis of the solid residues obtained after the slurry experiments of both pure caffeine and its cocrystal (Fig. 3 and 4) . The XRPD
patterns of both the residues were found to be identical but significantly
different from that of the original material (before slurrying in water) indicating that both the caffeine as well as its cocrystal converted to caffeine
hydrate upon slurrying in water for 24 h. Since, the hydrates exhibits lesser
solubility as compared to their anhydrous forms 29,30, therefore, concentration of caffeine achieved after slurrying in water is lesser than that reported
in literature.
Stability Studies
A comparison of the relative humidity stability of CAF-PA to that of
caffeine anhydrous was performed in order to assess whether this cocrystal
offered enhanced physical stability profiles. Analysis by XRPD as well as
FT-IR provided an effective means of monitoring the status of cocrystal
during this study. It was noted that cocrystal hydrate was not formed from
any of these cocrystals. Rather the materials that possessed instability
with respect to RH demonstrated dissociation of the cocrystal into its
starting components. The stability results of caffeine and CAF-PA under
various relative humidity (RH) conditions are summarized in Table 3.
Anhydrous ß-caffeine: Crystalline anhydrous caffeine was stored in humidity chambers alongside the cocrystalline material. XRPD and FT-IR patterns of the sample at 0 % RH did not show any peaks arising due to
hydration even after 4 weeks and the scans were found to be superimposable
with the original scan. Similarly the sample exposed to 43 % RH at 25 °C
showed no sign of hydration after 1 day. However, complete hydration of
anhydrous caffeine was observed after three days and beyond. As expected
at 75 and 98 % RH, caffeine converted to its hydrate completely after 1
day.
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Cocrystal CAF-PA: The XRPD and FT-IR scans of CAF-PA sample exposed to both 0 and 43% RH at 25 °C were found to be similar to the
original sample even after 4 weeks. There was no change in the XRPD and
FTIR scans of the cocrystal at 75 % RH till 3 days. However, the XRPD
scan of sample after 1 week showed growth of anhydrous caffeine as well
as caffeine hydrate evident by the appearance of new peaks and additionally the two characteristic peaks of cocrystal at 2510 and 1948 cm-1 were
missing in FTIR spectra obtained after 1 week. Further exposure upto
fourth week resulted in complete conversion of caffeine to its hydrate. At
98 % RH, CAF-PA showed full conversion to caffeine hydrate after 1 day
only. These results showed that though the cocrystal was not fully stable at
75 and 98 % RH but showed improved stability over anhydrous caffeine at
43 % RH.
CONCLUSION
A solution based cocrystallization experiment of caffeine with propionic
acid resulted in a new cocrystalline form which was characterized in solid
state by DSC/TGA, XRPD and FT-IR as well as in solution form by
solution calorimetry. The higher endothermic value of molar enthalpy of
solution of cocrystal suggested it to be thermodynamically favoured phase.
The RH stability profile of this cocrystal demonstrated a superior stability
to that of anhydrous caffeine at lower RH, although, unstable at higher RH.
ACKNOWLEDGEMENT
We gratefully acknowledge the financial support provided by University
Grants Commission (UGC), New Delhi, India, for accomplishing this work.
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Source of support: UGC, New Delhi, India, Conflict of interest: None Declared
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