Journal of Controlled Release, 9 (1989) 43-55 43

Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

CONTROLLED RELEASE NITROGLYCERIN CAPSULES

Himanshu R. Bhatt, M.L. Gurnasinghani, K.K. Dattani” and J.K. Lalla**

Department of Pharmaceutics, Principal K. M. Kundnani College of Pharmacy, Plot No. 4 7, Dr. R. G. Thadani Marg, Worli Sea
Face, Bombay-400 0 1B (India)

(Received July 15, 1987; accepted in revised form June 30, 1988)

Formulation and evaluation of controlled release nitroglycerin capsules are being reported. The
formulation aspects include evaluation of polymer membranes for drug diffusion, coating of sugar
beads with drug followed by rate-controlling membrane, and encapsulation in size 00 hard gelatin
capsules. The coated beads have been evaluated for surface topography, changes in dimensions
and in vitro drug release. The dosage form has also been investigated in vivo in human volunteers
using pulse plethysmography. The capsules were found to give controlled release of nitroglycerin
during 7 hours. Accelerated stability studies on the capsules during 3 months indicated that the
formulation lost only 4.7% of the drug at 50” C and 81% RH and did not show significant alter-
ation in the dissolution pattern.

INTRODUCTION release nitroglycerin oral formulation on the

strength of this observation.
Nitroglycerin, a propane-1,2,3-trio1 trini-
trate, is a potent vasodilator of great value in
the treatment and prophylaxis of angina pec-
toris. It reduces “preload” and “afterload” on EXPERIMENTAL
the heart thus reducing the oxygen consump-
tion. It is also used in congestive heart failure
and myocardial infarction. MATERIALS
One of the disadvantages of nitroglycerin is
its short duration of action when administered
sublingually [ 11. This has been obviated All the materials were used as supplied and
through introduction of sustained release ni- without further treatment. They were as fol-
troglycerin preparations which could be ob- lows. Nitroglycerin: A 10% lactose triturate (M/
tained using known methods [ 2-51. Turner [ 61 s Burroughs Wellcome India Ltd. ) . Sugar pel-
and other workers [7-111 observed that sus- lets: Size range 600-800 pm (Beck and Koll).
tained release products gave duration of action The following polymers were used: Poly (vinyl
longer than non-sustained tablets. alcohol) (PVA), hot water soluble: Cella-
We have attempted to prepare a controlled ce1@279 (Cellulose Products of India); ethyl-
ene-vinyl acetate copolymer (EVA-JV-2040)
(Hoechst Plastics, Frankfurt); Eudragit@ RS
*Deceased. (Rohm Pharma, GmbH, Darmstadt);
**To whom correspondence should be addressed. poly (vinyl pyrollidone ) - Kollidon@’ 30

0168-3659/89/$03.50 0 1989 Elsevier Science Publishers B.V.

44

TABLE 1
a PVA solution of fixed concentration and
Solubility of polymers varying its volume.
Free films of EVA were cast using a 2% w/v
Polymer Solvent”
solution of EVA in toluene plasticized with 2%
W MA A B C MEK EA T W+MA diethyl phthalate (DEP) (on the basis of solid).
+_ ---- ---
In this case, the drying procedure was slightly
PV
EVA + - _ + - modified. The polymer solution was not ex-
EC +++++ +-- posed to the IR lamp, but the evaporation of the
Eudragit RS - - + - + - - - - solvent was allowed to take place at room tem-
“W = water, MA = methyl alcohol, A = acetone, B = benzene, perature. The free films were then removed on
C = chloroform, MEK = methyl ethyl ketone, EA =ethyl acetate, the following day.
T = toluene.
Key: + = soluble, - = insoluble, + = soluble near boiling point.
Testing of the films
(BASF); ethyl cellulose (EC), 45% ethoxyl
content (BDH). Freshly prepared free PVA and EVA films
were conditioned by keeping them in a desic-
cator containing granular activated silica gel for
a period of one week prior to testing. They were
METHODS
evaluated for the following characteristics:

Determination of solubility a. Determination of thickness and area

The thickness of each film was measured in
About 1 g of the polymer was suspended in 25 the centre and around the periphery with a mi-
ml of solvent, allowed to stand for 24 hours at crometer. Their area was calculated by meas-
room temperature with occassional shaking and uring the diameter.
observed visually. In the event of insolubility,
the mixture was heated to almost the boiling b. Mechanical properties
point and observed to see whether the polymer ($ Burst strength: The burst strength of free
dissolved. The solubility data are shown in Ta- PVA and EVA films of varying thickness was
ble 1.
TABLE 2
Casting and evaluation of rate-controlling
Mechanical properties of films
PVA and EVA polymer films
Polymer Thickness Burst strength” Tensile strength”
Free films of PVA were cast by pouring the film Cum) (kg/cm’) kg/cm’)
polymer solution (2% w/v in water) in 4 in. PVA 30 4.5 110
Anumbra petri dishes. For enhancing the rate 50 5.0 11.0
of evaporation of solvent, drying conditions 70 NBb 11.5
were standardised. Drying was accelerated by
EVA 30 NBb VE”
placing an IR lamp (Philips 2A) at a fixed dis- 50 NBb VE’
tance of about 12 in. above the petri dishes. After 70 NBb VE
complete evaporation of the solvent, the petri
“Average of 3 determinations.
dishes were allowed to stand overnight at room
bNB: The film did not burst upto the maximum applied
temperature and the free films were removed pressure of 10 kg/cm’.
from the glass substrate on the following day. “VE: Very elastic, sample did not break even when the jaws
The thickness of the film was controlled using were at maximum distance apart.
 45

determined using a power-operated burst
strength tester described in ASTM Standard
774-67 (1968).
(ii) Tensile strength: The tensile strength of
rectangular strips of polymers of different
thicknesses was determined by constant rate of
grip separation methods as given under ASTM
Standard D-882-67 (1968) using a tensile tester
Model 1.4F KM1 (Kamal Metal Industries).
The results are given in Table 2.
c. Transmission through films
(i) Water vapour transmission: The method
employed to measure water vapour transmis-
sion was a modification of method described in
ASTM Test No. E96-53T given in part 27 using
Payne permeability cups. Free films with thick-
ness 30, 50 and 70 pm were employed in this
test. Each cup was filled with silica gel and a
polymer film was mounted over it. It was next
weighed and placed in a desiccator to give a pre-
determined humidity when stored at a defined
temperature. The temperature and the humid-
ity conditions are given as footnotes to Table 3.
The cups were then weighed at intervals of 24
hours for a period of 7 days and the increase in
weight (as an average of three samples) was re-
corded. From the data obtained, the rate of
water vapour transmission ( rM), water vapour
permeability (Q,) and moisture permeability
coefficient (P,) were calculated (Table 3 ).
(ii) Liquid water transmission: The films were
evaluated for liquid water transmission by the
method described under (i) above substituting
“self-indicating” silica gel by deionised water
(conductivity 10e7 S) in the cups and observ-
ing the usual precautions while mounting the
polymer film. The cups were kept in an inverted
position in a desiccator containing silica gel.
These desiccators were placed in a B.O.D. in-
cubator to maintain a temperature of 20 + 1 ‘C.
The loss in weight was recorded at intervals of
24 hours for a period of 6 days. Substituting the
values of water vapour by liquid water, the rate
of liquid water transmission (rlwt), liquid
permeability ( QL) and liquid permeability
coefficient (P,,,) were calculated (Table 4).

TABLE 3

Water vapour transmission and related parameters

Water vapour Type of polymer film

transmission constants
PVA PVA PVA EVA EVA EVA
(30 Pm) (50 Pm) (70 wn) (30 Pm) (50 Pm) (70 Pm)

rwt 23.40 22.20 15.60 9.70 7.10 7.00

(g/ (cm’ h mmHg) x 106) 5.55 4.46 4.18 3.95 2.39 1.72
121.90 120.50 100.70 55.20 53.40 38.40

QW 9.40 14.90 14.70 3.89 4.70 6.51

(g/(cm 24 h) X10”) ; 2.24 2.99 3.93 1.59 1.61 1.62
C 15.37 25.35 29.60 6.96 11.25 11.34

p, 7.00 11.20 10.90 2.89 3.53 4.89

(g/ (cm h mmHg) x 10s) ;: 1.67 2.23 2.92 1.18 1.20 1.20
C 36.57 60.36 70.50 16.50 26.70 22.00

a: Temperature, 40 k 1°C; humidity, 81.7%.

b: Temperature, 40 k 1°C; humidity, 60.0%.
c: Temperature, 30 f 1°C; humidity, 93%.
46

TABLE 4

Liquid water transmission and related parameters; temperature: 20 f 1 “C

Liquid water transmission Type of polymer film

constants
PVA PVA PVA EVA EVA EVA
(30 pm) (50 pm) (70 ,um) (30 ,um) (50 pm) (70 ,um)

rlwt (g/ (cm’ h mmHg) x 104) 3.02 2.93 2.84 1.94 1.65 1.40
QL (g/(cm 24 h) x10”) 3.80 6.15 8.30 2.44 3.46 4.12
P, (g/ (cm h mmHg) x 106) 0.93 1.42 2.00 0.57 0.82 0.98

TABLE 5 TABLE 6

Water content fraction Gas permeability data; temperature: 30 + 1 “C

Film Thickness Water content fraction Type of Thickness Weight Q,x 105
(pm) (%I film (pm) increase” (g/cm 24
(9) h)
PVA 30 66.6 (SD?O.66)
EVA 30 0.0 (SD+O) PVA 30 0.151 4.70
PVA 50 .129 6.70
Average of 5 determinations. PVA 70 0.121 8.80
EVA 30 0.110 3.42
d. Water content fraction (wcf) EVA 50 0.070 3.63
Since the rate of release of drug from hydro- EVA 70 0.063 4.58
gel dosage forms is governed by water content “Average of 3 determinations.
fraction of the polymer, it was considered im-
portant to determine this. Both polymer films
The films were mounted quickly on the cups.
were kept in separate containers filled with
The latter were then weighed accurately and
water for 24 hours. The films were carefully re-
placed in a vacuum oven (capacity 11.4 L) in
moved with the help of forceps, gently wiped
which silica gel was placed as desiccant. The
with filter paper on both sides and weighed ac-
oven was then secured tightly and high vacuum
curately. The films were then dried under re-
applied to remove all the air from it. Subse-
duced pressure to a constant weight. The wcf
quently, the vacuum was broken by passing car-
for each film was calculated as follows:
bon dioxide (the gas being passed over silica gel
wcf(%)=100X desiccant before it was admitted to the cham-
ber) into the oven chamber until a pressure of
(wet membrane weight - dry membrane weight)
about 600 5 10 mmHg was obtained. The in-
wet membrane weight
crease in weight of the cups due to the absorp-
The results are shown in Table 5. tion of carbon dioxide by potassium hydroxide
was recorded at the end of 24 hours exposure
e. Gas permeability studies (Table 6).
Carbon dioxide was selected as the experi-
mental gas for these studies. Potassium hy-
droxide pellets were dried in an oven at 120- f. Diffusion studies
130” C for over 2 hours. A fixed amount of these The diffusion cell: A specially designed stain-
pellets was kept in each Payne permeability cup. less steel diffusion cell fabricated in our labo-
 41

ratory was used to study the diffusion of nitro-
glycerin through two polymeric membranes. A
diagrammatic section of the cell is shown in Fig.
1.The horizontal cell consists of two similar
halves or horizontal compartments (donor and
receptor) of identical capacity (30 ml) and dif-
fusional area. Each of the compartments was
provided with a stirring shaft perpendicular to
the plane of diffusion and fitted with oil seal
rings to make them leak proof. Each of the com-
partments was provided with a sampling port
and was surrounded by a water jacket to main-
tain the temperature at 25 5 1 ‘C.
Diffusionprofile of nitroglycerin through PVA
and EVA films: The PVA and EVA film discs
were clamped between the two oil-seal rings
which were carefully placed in the cavity pro-
vided in one of the compartments of the cell.
Both the compartments were brought together
and secured tightly by means of screw thread-
ings at the mouth of each compartment. The
cell was fitted horizontally on the stand.
The right-hand side (receptor) compart-
ment was filled first with an accurately mea-
sured quantity of carbon dioxide free deionised
water. The left-hand side (donor) compart-
ment was filled with an accurately measured
quantity of aqueous nitroglycerin solution. The
amount of solution loaded was 30 ml. Fifteen-
milliliter samples were withdrawn at one hourly
intervals from the receptor compartment, the
solution being replaced with 15 ml of fresh me-
dium to maintain the volume. The samples were
analysed for the drug spectrophotometrically at
548 nm using the method suggested by Bell
1121.
Data analysis
From the data obtained earlier, solute flux
(J,) was calculated (see Tables 7-9, Figs. 2-4).
Preparation of controlled release
nitroglycerin capsules using sugar beads

The preparation procedure of controlled re-

lease nitroglycerin capsules can be divided in
cSampllnq Port
three steps: (a) Loading of the sugar beads with

TABLE 7
*Water Jacket
Diffusion of nitroglycerin through PVA film

Film thickness: 30 pm; feed solution: aqueous nitroglycerin

(1 mg/ml); quantity in diffusion cell: donor cell: 30 ml; re-
ceptor cell: 30 ml; sampling: 15 ml from receptor cell after
every hour; method of analysis: spectrophotometrically at
548 nm

Time, Drug concentration Differential Cumulative

t (mol X 106) release release
(h) (molX106) (molXl0”)
Donor Receptor
cell cell

0 132.15 0 0 0
$+&
w\ Samplinq

Stirrinq
Port

Shaft
1
2
3
4
117.70
107.99
102.42
94.16
14.45
16.93
14.04
15.28
14.45
9.71
5.58
8.25
14.45
24.16
29.74
37.99
5 89.00 12.80 5.16 43.16
Fig. 1. Engineering drawing of diffusion cell (bottom: cross- 6 83.51 11.89 5.49 48.65
section ) .
48

TABLE 8 TABLE 9

Diffusion of nitroglycerin through EVA films Diffusion of nitroglycerin through EVA films

Film thickness: a = 30 m, b = 60 pm; feed solution: aqueous
nitroglycerin (577 pg/ml); quantity in diffusion cell: (1)
donor cell: 30 ml; (2) receptor cell: 30 ml; sampling: 15 ml
from receptor cell after every hour; method of analysis:
spectrophotometrically at 548 nm
Film thickness: 30 pm; feed solution: aqueous nitroglycerin
(2 mg/ml); Quantity in diffusion cell: (1) donor cell: 30 ml;
(2) receptor cell: 30 ml; sampling: 15 ml from receptor cell
after every hour; method of analysis: spectrophotometri-
tally 548 nm

Time, Drug Differential Cumulative Time, Drug concentration Differential Cumulative

t concentration release release t (molesX 106) release release
(h) (molX 106) (molx 106) (molX 106) (h) (mol X 106) (molX 106)
Donor Receptor
Donor Receptor cell cell
cell cell
264.31 0 0 0
a 76.20 0 0 0 255.82 8.49 8.49 8.49
b 76.20 0 0 0 252.03 8.03 3.79 12.29
249.03 7.01 2.99 15.28
a 74.59 1.62 1.62 1.62 244.97 7.57 4.06 19.34
b 74.22 1.99 1.99 1.99 242.19 6.56 2.78 22.12
239.78 5.69 2.40 24.53
a 73.11 2.29 1.48 3.10
b 73.39 1.80 0.82 2.80

a 72.03 2.22 1.08 4.18

b 72.26 2.03 1.13 3.93

a 70.96 2.18 1.06 5.24

b 71.26 2.02 1.00 4.96

a 69.97 2.08 0.99 6.24

b 70.25 2.01 1.00 5.95

a 68.98 2.04 0.99 7.23

b 69.36 1.90 0.89 6.78

nitroglycerin. (b) Coating of nitroglycerin
beads with various polymer solutions. (c) En-
capsulating the polymer-coated beads in hard
gelatin capsules.
a. Loading of the sugar beads with
nitroglycerin
Sugar beads ranging in size from 600 to 800
pm were used for coating with nitroglycerin.
Nitroglycerin was extracted from 30 g of lactose
triturate by adding 100 ml dry methanol and
filtering. To the filtrate, 1.5 g of PVP was added
as a binder and the mixture was stirred until a
TIME IN HOURS
Fig. 2. Solute flux (J,) of nitroglycerin through PVA films.
Film thickness 30 pm; feed solution 1 mg/ml.
clear solution was obtained, which was subse-
quently used as a coating solution.
The sugar beads (300 g) were taken in a 6 in.
diameter conventional coating pan. After dust-
ing off the beads, the coating solution was
sprayed by means of a hydraulic spray gun.
Throughout the coating process, the size of the
nozzle of the spray gun, the pressure of air (12.5
psi), the duration of spraying and the time for
evaporation and drying of the solvent were kept
 were therefore made to use the polymers in
combination. The following combination was
found to give satisfactory release profiles: EVA,
1;Eudragit RS, 9; chloroform, q.s.100. EVA and
Eudragit RS were both separately dissolved in
chloroform. The two solutions thus obtained
were then mixed and the resulting clear mix-
ture was filtered through muslin cloth and used
as a coating solution. The procedure used for
coating was the same as described earlier.

I c. Encapsulation in hard gelatin capsules

00 1 2 3 4 5 6 7
TIME IN HOURS
Nitroglycerin controlled release beads (300
mg) representing 3 mg of the drug were encap-
Fig. 3. Solute flux (J,) of nitroglycerin through EVA films. sulated in size 00 hard gelatin capsules.
Film thickness (0, dashed line) 30 pm, (A, full line) 60
,um; feed solution 577 ,ug/ml.
Characteristics of the beads

Dimensions
The diameters of the beads were determined
microscopically under low power objective us-
ing a 10x eyepiece. The increase in diameter
due to coating with drug and with polymer was
noted. Using these data, the increases in vol-
ume and surface area were calculated (Table
10).

00
1 1 2 3 4 5 6
Nitroglycerin content determination
TIME IN HOURS The beads were also evaluated for the uni-
Fig. 4. Solute flux (J,) of nitroglycerin through EVA films. formity of nitroglycerin content. For this pur-
Film thickness 30 pm; feed solution 2 mg/ml. pose, 100 mg of beads were crushed and added
to a 100 ml volumetric flask. Water containing
constant in order to standardize the conditions 1% methanol was then added and the volume
of coating. The process was continued until adjusted to the mark. Aliquots (5 ml) were
about 300 mg of the sugar beads had a nitrogly- withdrawn and diluted to 10 ml; the amount of
cerin content of 3 mg. nitroglycerin in the aliquots was estimated
spectrophotometrically.
b. Coating of nitroglycerin beads with
various polymer solutions Surface topography of beads
Nitroglycerin-coated beads were then coated Scanning electron micrographs of the beads
with different coating materials namely ethyl were recorded on a Siemens scanning electron
cellulose, poly (vinyl alcohol), Eudragit RS and microscope to investigate the surface topogra-
ethylene-vinyl acetate copolymer. The drug re- phy of (i) plain sugar beads, (ii) sugar beads
lease from these polymer-coated beads was de- coated with nitroglycerin, and (iii) nitrogly-
termined in water at 37°C. None of the mate- cerin beads coated with EVA-Eudragit mixture
rials gave satisfactory release profiles. Attempts (Figs. 5A, B and C).
50

TABLE 10

Change in dimensions of beads due to coating

Sample VoIume Increase in Surface area Increase in

(mm”) volume (mm21 surface area
(mm3) (mm21

Sugar beads 0.175 (SDk0.0393) - 15039 (SD t- 0.2240)

Drug coated 0.211 (SD IO.048) 0.036” 1.7048 (SD C0.259) 0.2009~
EVA coated 0.271 (SD + 0.046) 0.06b 2.0435 (SD f 0.205 ) 0.3387b
WA coated 0.271 (SD rt0.047) 0.06s 2.0178 (SDLO.236) 0.313s
EC coated 0.251 (SD + 0.056) 0.04s 1.9121 (SD+O.284) 0.2073s
Eudragit RS
coated 0.256 (SD i 0.049) 0.045s 1.9365 (SD i0.248) 0.2317b
Eudragit RS
t-EVA coated 0.261 (SD-t-0.053) 0.05s 1.9656 (SDt0.271) 0,2608~

“With respect to sugar beads.

“With respect to drug-coated beads.

Dissolution profiles In vivo studies

The in vitro dissolution of the drug was de-

termined in 300 ml of purified water at 37 ‘C in
a USP XX dissolution rate test apparatus
equipped with a paddle. The latter was rotated
at 75 rpm. Samples were withdrawn at one
hourly intervals for 10 hours. The amount
withdrawn was replaced with fresh purified
water. In the withdrawn samples, the drug re-
leased was estimated employing the method de-
scribed earlier [ 121. The results are recorded in
Figs. 6 and 7.
Stabili~ studies
The polymer-coated beads were placed in un-
corked amber-coloured bottles in desiccators
maintained at relative humidities of 60% and
81% at 30, 40 and 5O”C, respectively, by satu-
rated salt solutions. Samples were withdrawn
at intervals of 3 weeks during 12 weeks. The
stored samples were evaluated for visual ap-
pearance, drug content and release profiles
(Table 11) . As a representive figure of the re-
lease profile, a plot of percent release vs time
for beads stored at 50’ C and 80% RH is shown
in Fig. 8.
Protocol
The study was u~de~~en in three healthy
male volunteers in the age group of 22-24 years.
The selected individuals were within 5% of their
ideal weight and weighed between 57 and 62 kg
(mean, 58.2 kg). Written informed consent was
obtained from all the volunteers. Each of the
volunteer was a non-smoker, had no history of
alcohol consumption and did not have any re-
ported abnormality of liver and kidney.
Each volunteer reported at the Clinical
Pharmacolo~ unit at 8 o’clock in the morning
on each of the experimental days. We was made
to lie down in a temperature-controlled room,
and then allowed to rest in supine position. The
bio-availability of the drug was determined us-
ing pulse plethysmography [13]. The pulse
transducer was positioned on the left middle
finger so that incident light was made to fall on
the same spot throughout that experimental day
and on subsequent days of study. After the rest
period, the pulse tracing was recorded at short
intervals of time until a constant value indi-
cated the stabilised state of the volunteers. It
was only after this that the dose was adminis-
 51

I 2 3 4 3 6 7 6 9 10
TIME IN HOURS

- RELEASE FROM EUDRAGIT COATED BEADS

- RELEASE FROM EVA COATED BEADS
o-----9 RELEASE FROM PVA COATED BEADS

- RELEASE FROM EC COATED BEADS

Fig. 6. In uitro dissolution profiles of nitroglycerin-impreg-

nated beads coated with various polymers.

100
r

1 2 3 4 5 6 7 6 9 10

TIME IN HOURS

Fig. 7. In oitro dissolution profile of nitroglycerin-impreg-

nated beads coated with Eudragi-EVA mixture.

tered to each of the volunteers as described

below.

Fig. 5. Scanning electron micrographs. A: uncoated sugar
beads (300 x ); B: nitroglycerin-coated sugar beads (300 X );
C: polymer-coated sugar beads (300 x ) .
Placebo administration
After the volunteer was in stabilised state, a
placebo was administered. Pulse tracing was re-
corded at 0,0.5, 1,2,3, .... 7 h post administra-
tion. The response variables were calculated
relative to the pre-drug values. For each vol-
unteer, mean pre-drug base-line variables in-
cluding a and b were calculated [ 131. The same
response variables were calculated for each post
52

TABLE 11

Stability studies data

No. of weeks Visual appearance %

Nitroglycerine

Room temperature - 60% RH

3 no change 100
6 no change 98.4
9 no change 97.2
12 no change 95.6

40” C - 60% RH
3 no change 100
6 no change 98.6
9 no change 97.0 - AT THE END OF 3rd WEEK

12 no change 95.5 - AT THE END OF 6th WEEK

- AT THE END OF 9th WEEK

4O”C-81% RH - AT THE END OF 12th WEEK
3 no change 100
6 no change 98.3
9 no change 96.4
12 no change 95.3 or
0
L
1
’
2 3
’ *
4
’
5
’
6
’
7
’
6 9
’ ’
10
- HOURS -
5O”C-60% RH
Fig. 8. Accelerated stability studies on controlled release
3 6 no change 100
nitroglycerin capsule. Temperature 50 oC; humidity 81%
9 no change 98.7
RR.
12 no change 97.3
no change 95.3

5O”C--81% RH a/b(corrected) =a/b(drug)

3 no change 100
-a/b (placebo in all three cases (a), (b) and (c) below)
6 no change 98.5
9 no change 97.6
12 no change 95.9
In the entire study, care was taken to see that
none of the nitroglycerin dosage forms were ad-
drug time intervals. The % a/b intensity was ministered before 7 days had elapsed from the
calculated as: time of a~inistration of an earlier dosage form
in order to flush out any drug remaining in the
a/b intensity (% )
body of the volunteer from the previous run
= 1oo x (post drug a/b - predmza/b) The three formulations mentioned below
predrug a/b were administered to each of the volunteers
separately:

Nitroglycerin dosage form administration (a) Sublingual administration: The volunteer

In order to compensate for the placebo base
line that may vary with time and to show better
relative drug effects, the a/b index was cor-
rected for placebo effects by substracting the
placebo a/b intensity value at the same point:
was administered nitroglycerin sublingual tab-
lets ( Angised Burroughs Wellcome India Ltd. )
containing 0.5 mg of nitroglycerin. The pulse
tracing was recorded at different time intervals.
(b) nitroglycerin controlled release capsule
 53

administration: A capsule representing 3 mg of

the drug was administered orally to the volun-
teer with 200 ml of water. Pulse tracing was re-
corded at time intervals of 0.5, 1, 2,3,4, . . .. 7 h
post administration of capsule.
(c) Administration of nitroglycerin market
preparation: Nitrobid, nitroglycerin sustained
release capsule (containing 2.6 mg nitroglycer-
ine), marketedby Marion Pharmaceuticals Inc.,
was administered and the pulse tracing was re-
Time
corded as described earlier.

L---J PLACEBO
A corrected a/b index vs. time profile from
0-d SUBLINGUAL 0.5 m6
different formulations is shown in Fig. 9. The
- SUSTAINED RELEASE NITROBID CAPSULE
- CONTROLLED RELEASE FORMULATION
results were extrapolated as described by Imhof
et al. [ 131 to give plasma level concentrations
Fig. 9. Pharmacodynamics of nitroglycerin formulations. (Fig. 10) to obtain the results represented
graphically in Fig. 11.

RESULTS AND DISCUSSION

The most important component of a con-

0.2 0.6 1.0 1.4 I.6 2’2 2.6
trolled release formulation is the rate-control-
- ng/ml ---+ ling membrane. The membranes investigated
Fig. 10. Plot of a/b vs plasma level. (Correlation values ob- included PVA and EVA.
tained from Imhof et al. [ 131.)
Membrane characteristics

3t As regards the diffusion-controlling mem-

brane, selection of the proper material is of ut-
most importance. Four commonly used poly-
mers viz. ethyl cellulose, PVA, EVA and
Eudragit RS were selected in this study. After
determining the solubility of these polymers in
various solvents, PVA and EVA films of various
thickness were cast after addition of 2% die-
thylphthalate as a plasticizer to EVA solution
cqo, 10 xl so 1 3 5 7
only. Eudragit films could not be removed from
-Minutes+ . liourrt-
-Time--c
the glass substrate on which they were cast.
Mechanical properties of PVA films were good
- SUBLINGUAL 0.5 mp.
(Table 2 ) , while EVA films were too elastic to
- SUSTAINED RELEASE NITROBID CAPSULE

6---a CONTROLLED R~~E.EFORMULATION enable determination of mechanical strength.

Different transmission values for these films
Fig. 11. Plasma level vs time profiles of nitroglycerin for- are recorded in Tables 3-6. These values will
mulations. (Plasma levels are extrapolated from Fig. 10.) ultimately help in deciding the humidity and
54
environmental conditions during manufactur-
ing and packing as well as the type of packing
used for the finished dosage forms. Liquid water
transmission assumes importance as its value
dictates the selection of which thickness of
membrane should be used not only to permit
the g.i. fluids to enter the coated beads after
administration but also to control the release of
the drug preferably at zero order. Results shown
in Table 4 indicate that a decrease in liquid
water transmission with increase in thickness
of the film was more pronounced with EVA than
with PVA, probably due to the hydrogel char-
acter of PVA. This is amply substantiated by
the water content fraction values which were
66% and 0% for PVA and EVA, respectively
(Table 5 ) . Gas permeability coefficient values
(Table 6) did not show much variation with
thickness of the film. In other words, the films
continued to be permeable even at higher thick-
nesses. This factor has to be carefully noted
while working with drugs which volatilise such
as nitroglycerin or get degraded in presence of
specific gases. Suitable packing has to be de-
signed in such cases.
Diffusion through membranes
Data for diffusion of nitroglycerin through
PVA and EVA membranes of different thick-
nesses (Tables 7-9) determined in a specially
designed cell (Fig. 1) indicated that EVA films
with a thickness of 30 or 60 pm did not show
significant difference in the amount of nitro-
glycerin diffusing through the membranes. Val-
ues of solute flux J, have been determined (Figs.
2-4).
Characterisation of beads
a. Surface topography
The surface topography of plain beads, nitro-
glycerin-coated beads and polymer-coa~d drug
beads recorded as scanning electron micro-
graphs (Fig. 5 ) indicated the presence of ridges
and craters on both the plain and nitroglycerin-
coated sugar beads. The craters decreased in
number after coating with film former indicat-
ing a slightfy nonuniformity of coating.
b. Nitroglycerin content
The sugar beads coated with nitroglycerin
showed an average content of 9.5 mg nitrogly-
cerin per gram of coated beads in three samples
drawn at random for analysis. Coating of these
beads with rate-controlling films using mix-
tures of EVA and Eudragit RS showed an av-
erage drug content of 8.57 mg per gram of beads.
c. In vitro dissolution profiles
The dissolution data presented in Figs. 6 and
7 indicated that the formulation employing a
mixture of Eudragit RS and EVA for coating
was most satisfactory, releasing almost 100% of
the drug in 10 hours. The percent release vs.
time profiles were linear. The release given by
the other coatings was far from satisfactory.
In viva studies
Studies on any formulation are incomplete
unless the performance of the system in uiuo in
humans is taken into account. An attempt was
therefore made to investigate the performance
of the formulation in human volunteers. As the
blood levels attained after the administration
of nitroglycerin sustained release formulations
are very low, there are technical difficulties in
determining the plasma concentration of nitro-
glycerin [13 1. A more rational approach is to
use the pharmacodynamic model in human vol-
unteers, in which therapeutic response is di-
rectly measured. A suitable method, viz. pulse
plethysmography, has been accepted by the
FDA (U.S.A.) as one of the methods for eval-
uation of nitrates. This method was followed
here. The results recorded in Fig. 9 indicated
that administration of sublingual tablets elic-
ited response for a period of about 1 hour only,
while the controlled release nitroglycerin cap-
sule showed response for the full period of 7
hours during which the release was studied. Due
to constraints, it was not possible to study the

release beyond 7 hours. Using the results ob-
tained in pulse plethysmography, the da/b in-
dex was correlated with plasma level concen-
trations as suggested by Imhof et al. [ 131.The
extrapolated results are shown in Fig. 11. The
results indicated that a peak value of 2.5 ng/ml
was obtained from a sublingual tablet 10 min-
utes post administration. The controlled re-
lease nitroglycerin capsule, on the other hand
showed peak plasma levels of 0.66 ng/ml at the
end of 30 minutes post administration followed
by attainment of a steady state level (C,,) of
about 0.44 ng/ml up to 7 hours. Similar results
were also obtained in case of Nitrobid capsules.
It will be observed from the results that even
though a/b index (corrected) showed a positive
value at the end of the 7th hour, the extrapo-
lated results showed zero plasma level. In other
words, despite the plasma level concentrations
of nitroglycerin being zero, the continued ther-
apeutic activity indicated that the extrapola-
tion of a/b index to serum level concentration
could not always be done.
Accelerated stability studies
The results of accelerated stability studies
were quite encouraging. The results of nitrogly-
cerin content analysis (Table 11) showed a loss
of about 4.4% to 4.7% at the end of 12 weeks of
storage at 30, 40 and 50” C and 60% and 81%
RH. However, this loss did not alter the disso-
lution pattern significantly, indicating thereby
that neither high temperature nor high humid-
ity had any profound effect on the degradation
of nitroglycerin.
ACKNOWLEDGEMENT
The authors thank the Hyderabad (Sind)
National Collegiate Board for providing labo-
ratory facilities, Searle India Ltd., Burroughs
Wellcome India Ltd. and Hoechst India Ltd. for
55
samples of the drugs, the late Dr. K.K. Dattani
and his colleagues and our colleagues who ac-
cepted to be volunteers in this study.
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