Effect of pharmaceutical excipients on the stability of trichlormethiazide tablets under humid conditions

Article abstract of DOI:10.1248/cpb.57.1343

The stability of trichlormethiazide (TCM) and the drug in the nine products available on the market (the original tablet (B) and 8 generic tablets (G1-G8)) were investigated under humid conditions. TCM was non-hygroscopic and was not degraded under humid conditions. Drug degradation in aqueous ethanol was accelerated with increased water concentration, and the drug stability in buffer solution was improved with decreased pH. TCM decomposition was not detected in each unwrapped tablet at low relative humidity. However, rapid degradation was observed for products G1 and G2, while product B and G7 showed higher stability at high relative humidity. The stability of products G1 and G2 decreased with increasing humidity. The same results were observed for the tablets in press-through packages (PTP), but the degradation rate was much slower than tablets without PTP packages. These results suggested that the adsorbed moisture by excipients cause TCM degradation. Various pharmaceutical excipients are added to TCM tablets and these vary between different pharmaceutical companies. Intact drug and pharmaceutical excipients, including lactose, microcrystalline cellulose, corn starch, hydroxypropylcellulose (HPC), low substituted HPC (L-HPC), calcium stearate, and light anhydrous silicic acid, were mixed, and the sample mixtures were stored in humid conditions. It was found that the TCM content decreased significantly in a binary mixture of TCM/HPC 1:1.

Full text of DOI:10.1248/cpb.57.1343

December 2009
Chem. Pharm. Bull. 57(12) 1343—1347 (2009)
1343
Effect of Pharmaceutical Excipients on the Stability of Trichlormethiazide
Tablets under Humid Conditions
Reiko TERAOKA, ,a Yuki MATSUSHIMA,a Isao SUGIMOTO,b Kana INOUE,a Shin-ya MORITA,a and
*
a
Shuji KITAGAWA
a Department of Pharmaceutical Technology, Kobe Pharmaceutical University; and b Educational Center for Clinical
Pharmacy, Kobe Pharmaceutical University; Motoyama-kitamachi 4–19–1, Higashi-nada, Kobe 658–8558, Japan.
Received May 1, 2009; accepted September 11, 2009; published online September 24, 2009
The stability of trichlormethiazide (TCM) and the drug in the nine products available on the market (the
original tablet (B) and 8 generic tablets (G1—G8)) were investigated under humid conditions. TCM was non-hy-
groscopic and was not degraded under humid conditions. Drug degradation in aqueous ethanol was accelerated
with increased water concentration, and the drug stability in buffer solution was improved with decreased pH.
TCM decomposition was not detected in each unwrapped tablet at low relative humidity. However, rapid degra-
dation was observed for products G1 and G2, while product B and G7 showed higher stability at high relative
humidity. The stability of products G1 and G2 decreased with increasing humidity. The same results were ob-
served for the tablets in press-through packages (PTP), but the degradation rate was much slower than tablets
without PTP packages. These results suggested that the adsorbed moisture by excipients cause TCM degrada-
tion. Various pharmaceutical excipients are added to TCM tablets and these vary between different pharmaceu-
tical companies. Intact drug and pharmaceutical excipients, including lactose, microcrystalline cellulose, corn
starch, hydroxypropylcellulose (HPC), low substituted HPC (L-HPC), calcium stearate, and light anhydrous sili-
cic acid, were mixed, and the sample mixtures were stored in humid conditions. It was found that the TCM con-
tent decreased significantly in a binary mixture of TCM/HPC 1 : 1.
Key words trichlormethiazide; stability; excipient; hydrolysis; adsorbed water
Trichlormethiazide ((3RS)-6-chloro-3-dichloromethyl-3,4- parts to titrate dose of the drug by prescription. The docu-
dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-diox- mentation on stability in the package insert for tablets avail-
ide) (TCM) is a thiazide diuretic drug that is used in the able in Japan differs among pharmaceutical companies.
treatment of hypertension. TCM has a steady hypotensive ef-
The purpose of the present investigation was to evaluate
fect in long-term therapy in combination with b-receptor the stability of TCM in a solid state with excipients and
blocking agent and angiotensin converting enzyme inhibitor. tablet products in detail under various storage conditions to
Different types of 2 mg TCM-containing tablets are available establish a reasonable stabilization design. The information
from 10 pharmaceutical companies in Japan.
obtained from these stability tests will be useful for the stabi-
The hydrolysis of hydrochlorothiazide and two other hy- lization of dosage forms.
drochlorothiazides was reported over a pH range 1 to 13 and
gave a bell-shaped pH rate profile.1,2) Yamana et al. also re-
ported on the decomposition of hydrochlorothiazide in solu-
tions with various pH values.3,4) The stability of TCM incor-
porated into gelatin gels was studied, and the hydrolysis rate
Experimental
Materials Bulk trichlormethiazide (TCM) was obtained from Iwaki
Seiyaku Co., Ltd. and used without further purification. Silicon dioxide
(Wako Pure Chemical Industries, Ltd.), calcium stearate (Wako Pure Chemi-
cal Industries, Ltd.), hydrated silicon dioxide, light anhydrous silicic acid,
of TCM in the gels was found to depend on the amount of hydroxypropyl starch (Freund Corporation), synthetic aluminum silicate
free water available for the reaction.5)
As reported previously, the stability of active ingredients
can be affected by pharmaceutical excipients. Aspirin degra-
(Takeda Pharmaceutical Company Ltd.), magnesium aluminometasilicate
(Fuji Chemical Industry Co., Ltd.), corn starch (Kanto Chemical Co., Inc.),
lactose (DMV International), microcrystalline cellulose (Asahi Kasei
Chemicals Co.), talc (Nacalai Tesque, Inc.), carmellose, carmellose calcium
dation in solid dispersion with urea or povidone was acceler-
ated by the adsorbed water onto the two carriers.6) The loss
of ascorbic acid increased progressively with increasing
moisture content in a mixture of silica gel and ascorbic acid
stored for 3 weeks at 45 °C.7) The extent of hydrolyzed hy-
drochlorothiazide was decreased by the addition of amino-
disulfamide.8) The hydrolysis of TCM in silk fibroin gel pre-
pared in various sugar solutions (such as ribose, fructose,
mannose, and glucose solutions) was studied. It was revealed
that the hydrolysis rate of TCM decreased in the following
order: riboseꢀfructoseꢀmannoseꢀglucose and the hydroly-
sis rate constant decreased with an increase in number of the
equatorial OH groups.9) However, TCM in solid state has not
been studied in detail, although the dosage form of the drug
is marketed as tablet in Japan. The tablets are removed from
(Gotoku Chemical Co., Ltd.), hydroxypropylcellulose (Shin-Etsu Chemical
Co., Ltd.), and low substituted hydroxypropylcellulose (Nippon Soda Co.,
Ltd.) were used as pharmaceutical excipients. The commercial solvents for
HPLC analysis, dehydrated ethanol, methyl p-hydroxybenzoate as an in-
ternal standard, and other chemicals were of reagent grade. The original (B)
and 8 generic products (G1—G8) of commercial TCM tablets were pur-
chased.
Stability of TCM Solution TCM (100 mg) was dissolved in 100 ml of
ethanol containing 0—30% (v/v) water. An aliquot of the solution (4 ml)
was placed in a glass vial and sealed hermetically. The samples were stored
at 35, 45, 50, or 60 °C in a constant temperature oven. The kinetics studies
of TCM degradation were determined in the following aqueous solution
(ionic strength adjusted to 0.5 M with sodium chloride): hydrochloric acid
(pH 0.8—2.0), sodium acetate (pH 3.6—4.5), and sodium dihydrogenphos-
phate (pH 5.3) buffers. Drug ethanol solution (0.2 ml of 10 mg/ml) was
added to 9.8 ml of each buffer solution, and the solutions were stored at
50 °C in a shaking constant-temperature water bath.
Stability of TCM in a Solid State TCM (10 mg) was weighed accu-
press through package (PTP) and divided into two or four rately into a small cup with a diameter of 30 mm and the cup was stored in
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: teraoka@kobepharma-u.ac.jp

1344
Vol. 57, No. 12
an airtight box with silica gel or a saturated solution of an inorganic salt to
control the relative humidity (RH) at 50 °C. The inorganic salts were
MgCl2·6H2O (30% RH), NaCl (75% RH), and KNO3 (85% RH).
The mixed powder of TCM and each excipient (20 mg; 1 : 1), 9 TCM
tablets with and without PTP, divided tablets, and pulverized tablet powders
were also stored in the same airtight box. The tablets were divided into half
tablets by using the tablet cutter (HCL #7347, Health Care Logistics INC.)
and pulverized into the fine powder using a pestle and mortar.
Assay Procedures for TCM The assay for the TCM content in the sam-
ples after storage was carried out using an HPLC system (Waters Co.)
equipped with Pump 515 and Dual Absorbance Detector 2487 (256 nm, Wa-
ters Co.); a prepacked column (SunFireTM C8 5 mm, 150 mmꢁ4.5 mm i.d.,
Waters Co.) was operated at room temperature at a flow rate of 1.0 ml/min.
The mobile phase was composed of acetonitrile : 0.1% (v/v) phosphoric acid
(1 : 3). A solution of methyl p-hydroxybenzoate in the mixed solution of ace-
tonitrile and water (9 : 1) was used as an internal standard. After storage, an
internal standard solution was added to the sample and stirred until the sam-
ple completely dissolved. The concentration of unchanged TCM was deter-
mined chromatographically using a stock solution. The mean of values de-
termined in triplicate was used.
Fig. 1. Effect of Water Concentration on Percent Remaining of TCM in
Ethanol at 50 °C
Water concentration, % (v/v): ꢀ, 0 ꢁ, 10 ꢂ, 15 ꢃ, 20 ꢄ, 30.
Water Vapor Sorption Isotherm Measurement The water vapor sorp-
tion isotherm of various excipients and the pulverized powders of commer-
cial tablets were determined at 50 °C using a dynamic vapor sorption system
(DVS) (Surface Measurement Systems Ltd.), which provides extremely ac-
curate gravimetric moisture sorption with a control of relative humidity and
temperature.
NMR and MS Spectrometry NMR spectra in DMSO-d6 were recorded
using a Varian VXR (500 MHz) with TMS as internal standard. Mass spec-
tra were measured using a Hitachi M-80.
Data Analysis The remaining of each generic tablet after storage was
compared with that of the brand tablet using the Dunnet’s test. Statistical
analysis for regression slope and correlation coefficient was performed by
using comparison of two regression parameters and the Pearson correlation
coefficient.
Results and Discussion
Effect of Water Content in Ethanol on the TCM Degra- Fig. 2. Effect of Water Concentration on the TCM Degradation Rate Con-
stants (kobs) in Ethanol at Various Temperatures
dation It is described in the Japanese Pharmacopeia, Fif-
teenth Edition that TCM is slightly soluble in 95% ethanol
Water concentration, % (v/v): ꢁ, 10 ꢂ, 15 ꢃ, 20 ꢄ, 30.
and practically insoluble in water. In the present study, the
effect of water on TCM degradation was investigated in
ethanol by altering the water concentration. Figure 1 shows
semi-logarithmic plots of the degradation profiles of TCM in
ethanol with various water concentrations at 50 °C. Straight
lines were obtained for each water concentration, suggesting
that degradation of TCM in aqueous ethanol followed first-
order kinetics. There was little change in the residual amount
of TCM in dehydrated ethanol and 97.2% of intact TCM re-
mained after storage for 48 h. On the other hand, TCM de-
graded quickly in ethanol containing water, and the amount
of TCM decreased to approximately 11.2% with a water con-
centration of 30% (v/v) after the same storage time. These
results indicated that TCM is unstable in aqueous ethanol.
The degradation rate constants calculated from the slopes
of the regression lines in Fig. 1 are plotted against water con-
centration at various temperatures in Fig. 2. The degradation
Fig. 3. Arrhenius Plots for the TCM Degradation in Ethanol Containing
Various Concentrations of Water
rate constant increased with increasing water concentration
Temperature (°C): ꢁ, 35 ꢂ, 40 ꢃ, 50 ꢄ, 60.
at every temperature. The value increased significantly at
higher temperature compared with low temperature, indicat- was 88.3 kJ/mol similar to the hydrolysis of penicillin10) and
ing that TCM degradation attributed to water was affected by cefadroxil.11)
temperature.
Effect of pH on TCM Degradation in Buffer Solution
The effect of the addition of water on the degradation of There are many previous reports on the effect of pH on drug
TCM is shown as Arrhenius plots in Fig. 3. The plots show- degradation in solution. Hydrochlorothiazide stability of a
ed good linearity for all water concentrations at 35—60 °C, benzothiadiazine analog like TCM was studied by Mollica et
and no significant difference among the activation energy al.2) and Yamana et al.4) Mollica et al.2) presented a bell-
values was observed, and the average activation energy shaped pH-rate profile for hydrolysis of the drug. The pH

December 2009
1345
Chart 1. Reaction Mechanism of TCM in Aqueous Ethanol
Fig. 4. The Effect of pH on the Degradation of TCM in Various Buffer
Solutions at 50 °C and Ionic Strength 0.5
Fig. 6. Stability of Intact TCM under Various Humid Conditions at 50 °C
and Water Sorption (%) of TCM Measured at Each Relative Humidity by
Dynamic Vapor Sorption System
Fig. 5. Changes in HPLC Chromatogram of TCM in Aqueous Ethanol at
50 °C
Storage time: (a) 0 h, (b) 12 h, (c) 24 h.
profile curve of TCM (Fig. 4) shows that with increasing pH
value, the degradation rate constants increased and that the
constants were the same value approximately at a pH of more
than 3.5, as also seen for hydrochlorothiazide. These data es-
timated that an imine intermediate exists in the hydrolysis re-
action, and a carbinolamine was formed by water or hydrox-
ide as with hydrochlorothiazide. The effect of pH on the
TCM degradation was not investigated in a pH of more than
5.3, because TCM precipitated at this pH value.
Figure 5 shows the chromatograms resulting from the
HPLC analysis of samples stored in water–ethanol (10% v/v)
at 50 °C. The peak of the degradation product after storage
was detected at 3.3 min in addition to the TCM peak at
12.5 min, and the peak intensity of the degradation product
increased with increasing storage time. The molecular for-
mula was determined to be C6H8ClN3O4S2 from HR-EI-MS
Fig. 7. Stability of TCM Tablets without PTP at Various Relative Humidi-
ties and 50 °C
∗ pꢂ0.05 compared with B.
of the degradation product isolated by preparative HPLC, namic vapor sorption system. Solid state TCM was ex-
showing a molecular ion peak at m/z 284.9632 (Calcd for tremely stable in all humid condition. This was attributed to
1
C6H8ClN3O4S2, 284.9645). The NMR spectrum (DMSO-d6) the fact that the amount of water absorbed by solid-state
showed two aromatic protons, as a singlet at d 6.97 and 8.16, TCM was extremely low under humid conditions, and it was
and 6 amine protons as a broad singlet at d 6.61, 7.34, and practically insoluble in water. In fact, water sorption (%) of
7.49. These data indicated that TCM was hydrolyzed by the TCM was lower than 0.10% at 85% RH (Fig. 6).
water to give 4-amino-6-chlorobenzene-1,3-disulfonamide
(Chart 1) as with the hydrolysis of hydrochlorothiazide.
Effect of Relative Humidity on the Stability of TCM
Tablets without PTP The B and generic drug (G1—G8)
Effect of Humidity on the Stability of TCM in the Solid contain 2 mg of TCM with lactose and other excipients. HPC
State TCM is used in a tablet dosage form in Japan. Figure was added with G1, G2, G3, G4 and G6. Figure 7 shows the
6 shows the remaining (%)TCM after storage in relative hu- remaining (%)TCM in 9 tablets without PTP after storage for
midities between 0% and 85% after 2 weeks, and water sorp- 2 weeks under various humidities at 50 °C. All products
tion (%) at each relative humidity was measured using a dy- showed no change in the remaining (%)TCM at 0% and 30%

1346
Vol. 57, No. 12
Table 1. TCM Remaining in Tablets with or without PTP, Divided Tablets,
and Pulverized Powder after 2 Weeks Storage at 85% RH and 50 °C
Table 2. Degradation (%) of TCM in the Presence of Various Additives,
Water Adsorption (%) of Additives on 85% RH and pH of Additive Solution
Divided Pulverized Adsorbed
Degradation,
%
Water
adsorption, %
Products
PTP (ꢃ)
PTP (ꢄ)
Additive
pH
tablet
powder
water
B
94.2ꢅ1.0 94.4ꢅ0.1 92.1ꢅ1.4 89.6ꢅ1.4
84.0ꢅ0.2 52.1ꢅ0.4 53.0ꢅ0.3 50.1ꢅ0.6
89.9ꢅ6.9 53.9ꢅ0.3 52.3ꢅ0.2 48.2ꢅ1.1
91.0ꢅ0.5 79.2ꢅ1.2 79.0ꢅ0.3 72.7ꢅ0.8
93.8ꢅ1.4 84.8ꢅ0.5 85.7ꢅ0.7 82.0ꢅ0.7
95.3ꢅ0.4 87.5ꢅ0.7 82.1ꢅ1.1 82.9ꢅ0.9
95.3ꢅ1.5 75.8ꢅ1.0 75.5ꢅ1.7 74.5ꢅ0.5
96.4ꢅ0.7 92.8ꢅ2.0 90.2ꢅ0.8 89.7ꢅ1.0
89.3ꢅ0.4 81.5ꢅ0.8 81.9ꢅ1.4 63.9ꢅ2.3
6.13
8.34
8.81
2.70
10.24
6.02
4.75
9.70
11.11
Hydroxypropylcellulose (HPC)
Synthetic aluminum silicate
Magnesium aluminometasilicate
Hydrated silicon dioxide
Low substituted HPC
Corn starch
Light anhydrous silicic acid
Microcrystalline cellulose
Carmellose calcium
Hydroxypropyl starch
Carmellose
15.9
3.5
3.5
3.3
2.9
2.9
2.1
0.9
0.0
0.0
0.0
0.0
0.0
0.0
0.0
16.3
30.5
33.0
28.2
20.0
19.4
14.0
10.3
23.9
20.1
19.2
2.6
5.3
6.8
7.8
3.7
5.7
4.8
6.8
6.1
4.6
6.6
3.7
7.1
7.5
4.5
5.9
G1
G2
G3
G4
G5
G6
G7
G8
Calcium stearate
Talc
Lactose
Silicon dioxide
RH. On the other hand, TCM degradation was observed in all
tablets after stored at 75% and 85% RH after storage for 2
weeks and the remaining TCM was decreased significantly
compared with B in all generic tablets except for G7. In par-
ticular, the TCM content was declined in G1 and G2 to 50%
0.2
0.1
0.1
after 2 weeks stored at 85% RH. The water sorption in the silicon dioxide, while the adsorption of water was observed
each pulverized powder of the tablets was measured using with other additives, and magnesium aluminometasilicate,
DVS at 50 °C and 85% RH (Table 1). The TCM remaining synthetic aluminum silicate, and hydrated silicon dioxide had
(%) in tablets with and without PTP, divided tablets, and in high moisture contents. The absorbed water content was
pulverized powder after 2 weeks storage at 85% RH and 16.3% on hydroxypropylcellulose, which that showed the
50 °C is summarized in Table 1. The adsorbed amount of highest degradation % of TCM. These findings suggested
water was not the same value among the 9 products. The sta- that TCM degradation could not be estimated directly from
bility of TCM can be improved by use of PTP. The remaining the water content adsorbed on additives.
(%) of drug in undivided tablets without PTP was equal to
The pH values of 5% (w/v) water solution or suspension
that of divided tablets. The remaining values were much of additive were measured, and the pH values of hydroxy-
lower in the pulverized powders of tablets, because the area propylcellulose, synthetic aluminum silicate, magnesium alu-
for water absorption was increased by grinding. Although the minometasilicate, and hydrated silicon dioxide were 5.3, 6.8,
TCM content in the solid state was scarcely changed at high 7.8, and 3.7, respectively (Table 2). These findings suggested
relative humidity, as described above, TCM in tablets was de- that the pH of the mixture with adsorbed moisture was incon-
graded at high relative humidity, indicating that the degrada- sistent with TCM degradation (%), i.e., 15.9% of TCM de-
tion may be attributed to the water adsorbed by excipients graded with hydroxypropylcellulose compared with 3.5%
contained in the tablets.
with magnesium aluminometasilicate. The hydrolysis rate of
Effect of Additives on TCM Stability under High Hu- nitrazepam was controlled by the N adsorption energy of the
midity Conditions A lot of different excipients are used in excipients, such as microcrystalline cellulose, corn starch,
brand and generic tablets; the excipients containing in each mannitol, and saccharose.15) The aspirin degradation rate in
tablet differ according to the manufacturer. The brand tablet binary mixtures with cellulose was affected by the brand of
contains seven kinds of additives, whereas more additives cellulose, and microcrystalline cellulose gave a higher degra-
were used in generic products. Castello and Nattocks12) re- dation with aspirin compared with microfine cellulose, be-
ported that the coloration with aging in tablets containing cause the microcrystalline cellulose-sorbed water was not
lactose (I) and amine salts (II) was due to the reaction of I tightly bound to the excipient.16) Hydroxypropylcellulose
with the free amine base liberated from II by an alkali lubri- gave a higher degradation rate for TCM than low substituted
cant, such as magnesium stearate. Gold and Campbell13) re- hydroxypropylcellulose. Yoshioka et al. demonstrated that
ported that different talcs of USP grade varied significantly the hydrolysis rate of trichlormethiazide in gels was found to
in their effects on the stability of aspirin in tablets. Thus, depend on the amount of free water available for the
drug stability could be affected by various additives. Equal reaction.5) It was estimated that the amount of free water on
mixtures of TCM and the excipient contained in brand and hydroxypropylcellulose was higher than that on low substi-
generic tablets were stored at 85% RH and 50 °C for 2 weeks tuted hydroxypropylcellulose from their report.
(Table 2). TCM degraded with 8 out of 15 additives, i.e., hy-
The Effect of Hydroxypropylcellulose on TCM Stabil-
droxypropylcellulose, synthetic aluminum silicate, magne- ity in Tablets In Fig. 8, the degradation rate constant of
sium aluminometasilicate, hydrated silicon dioxide, low sub- TCM vs. water adsorption is plotted for tablets with or with-
stituted hydroxypropylcellulose, corn starch, light anhydrous out hydroxypropylcellulose. A straight line was formed, indi-
silicic acid, and microcrystalline cellulose. In particular, the cating that the degradation rate constant was tightly related to
degradation % of TCM increased to close to 15.9% with hy- water adsorption. The slope of the regression line for tablets
droxypropylcellulose. The more additives adsorbed water, containing hydroxypropylcellulose was approximately four-
the more the drug stability decreased.14) The water adsorp- fold higher in tablets without hydroxypropylcellulose and
tion (%) of 15 additives at 85% RH measured by DVS is significant differences in slope were found between with and
shown in Table 2. Water was not adsorbed on talc, lactose, or without hydroxypropylcellulose. This result indicated that

December 2009
1347
lected carefully in formulation design, because the TCM
content decreased as a result of water adsorbed on the phar-
maceutical excipients.
Acknowledgement The authors are grateful to Freund Corporation, Go-
toku Chemical Co., LTD., Nippon Soda Co., Ltd., and Shin-Etsu Chemical
Co., Ltd. for providing the pharmaceutical excipients.
References
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Fig. 8. Relationship between TCM Degradation Rate Constants and Water
Adsorption at Various Humidities and 50 °C
ꢂ, HPC(ꢃ) ꢁ, HPC(ꢄ). ∗ pꢂ0.05.
TCM stability in tablets was decreased by hydroxypropylcel-
lulose under humid conditions.
11) Tsuji E, N. A., Deguchi Y., Nishide K., Shimizu T., Horiuchi S.,
Ishikawa K., Yamana T., J. Pharm. Sci., 70, 1120—1128 (1981).
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Conclusions
TCM in a solid state was stable under humid conditions,
but TCM in tablets were not stable under the same condi-
tions. TCM degradation was accelerated by the addition of
hydroxypropylcellulose. Various factors that may affect the
TCM stability in tablets can be considered such as adsorption
water, amount of free water, pH and so on.
15) Perrier P. R., Kesselring U. W., J. Pharm. Sci., 72, 1072—1074 (1983).
16) Ahlneck C., Alderborn G., Acta Pharm. Suec., 25, 41—52 (1988).
These findings suggested that the excipient should be se-