The document summarizes the preparation and evaluation of spherical agglomerates of hydrochlorothiazide using the neutralization method. Various formulation and process parameters were optimized to obtain spherical agglomerates with improved flow and compression properties compared to the drug alone. The optimized formulation F6 containing PVP K30 showed significantly improved solubility and dissolution profile of the drug. In conclusion, the spherical agglomeration technique helped render the poorly compressible drug suitable for direct compression into tablets.

1. “PREPARATION AND
EVALUATION OF
DIRECTLY
COMPRESSIBLE
2nd EVALUATION SEMINAR
SPHERICAL
AGGLOMERATES OF
HYDROCHLOROTHIAZIDE
Presented by: ”
SHANKAR.GAVARO Under the
JI guidance of
M.PHARM 2nd Dr. B.G.Desai
YEAR
PHARMACEUTICS

2. CONTENTS
• Introduction
• Need for study
• Methodology
• Optimization
• Formulation
• Evaluation
• Conclusion
• Review of Literature

3. Spherical
Agglomeration

4. Need for study
• Spherical agglomeration process is a multiple unit
process in which crystallization, agglomeration and
spheronization can be carried out simultaneously in one
step.
• The resultant crystals obtained show better solubility
profile, flow properties, and compressibility
• Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a
first-line diuretic drug of the thiazide class that acts by
inhibiting the kidneys' ability to retain water.
• It is variably absorbed from GI tract and has got
bioavailability of ~ 70%.
• Hydrochlorothiazide suffers from poor flow and

5. Preparation of agglomerates by
Neutralization method
• A solution of hydrochlorothiazide in 20%
NaOH (1.0g in 3ml) was added to distilled
water (30 ml) containing dissolved
polymer.
• Neutralization was done by adding 0.1M HCl
solution drop wise into the above solution
at room temperature.
• After the completion of neutralization
bridging liquid (DCM) was added drop wise.
• The mixture was stirred at 600 rpm using a
controlled speed stirrer for 30 minutes.
• The agglomerates formed were then
separated by filtration and dried at room

6. Calibration curve of
Hydrochlorothiazide

7. Preformulation studies
PARAMETER VALUE
Bulk Density (gm/cm3) 0.391±0.02
Tapped Density (gm/cm3 0.624±0.01
Hausner’s ratio 1.60
Carr’s Index 37.61
Angle of repose 46.340±0.120
* The values represent mean SD, n = 3

8. Solubility Study
Medium Solubility(mg/ml)
Water 0.71 0.01
0.1M HCl 0.24±0.006
20% NaOH 810±5
Dichloromethane 7.11±0.002
* The values represent mean SD, n = 3

9. Optimization

10. o Effect of bridging liquid on properties of agglomer
Bridging liquid Observation
Agglomerates were very fine, irregularly
Toluene
shaped with poor flow properties.
Process of agglomeration was time
Chloroform
consuming and agglomerates were sticky.
Agglomerates formed were spherical, free
Dichloromethane
flowing with good micromeritic properties.

11. o Effect of temperature on properties
of agglomerates:
Temperature (oC) Observation
Sticky and fragments like masses
5
formed
Very few agglomerates with
15
irregular shape and size formed
Agglomerates formed with good
Room temperature*
yield, shape and size.

12. o Effect of stirring (agitation) speed on
properties of agglomerates:
Speed (rpm) Observation
Agglomerates formed, but are very
High (above 1200)
fine.
Free flowing agglomerates with good
Medium (600-900)
sphericity.
Agglomerates formed, but the shape
Low (below 300)
and size are irregular.

13. Formulation

14. Ingredients F0 F1 F2 F3 F4 F5 F6 F7 F8 F9
Hydrochlorothiazide 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
(g)
PEG 6000 (mg) - 100 200 300 - - - - - -
PVP K30 (mg) - - - - 100 200 300 - - -
HPMC K4M (mg) - - - - - - - 100 200 300

15. Characterization of
agglomerates
• FTIR
• DSC
• SEM

16. EVALUATION

17. Pre-compression
parameters
o Yield and drug content of
agglomerates:
Yield Drug content
Formulation Particle size (µm)
(%) (%)
F0 80.56 95.78 158.6 3.27
F1 85.92 97.24 281.5 1.14
F2 82.15 97.10 227.51 1.31
F3 81.64 96.87 251.0 1.24
F4 86.10 97.10 237.4 1.53
F5 83.49 97.02 196.3 2.72
F6 88.47 96.52 275.1 1.34
F7 85.54 96.32 246.38 3.71
F8 83.23 95.74 256.1 2.32
F9 87.84 95.22 289 6.59
* The values represent mean SD, n = 3

18. o Flow properties
Bulk Tapped density* Carr’s Hausner’s
Formulations
density* (gm/cc) (gm/cc) index (%) ratio Angle of repose
Pure drug 0.391±0.02 0.624±0.01 37.61 1.60 46.340±0.120
F0 0.348 0.04 0.468 0.02 25.64 1.34 29.47 0.121
F1 0.365 0.02 0.384 0.05 4.94 1.05 12.35 0.403
F2 0.340 0.06 0.365 0.03 6.84 1.07 15.42 0.215
F3 0.384 0.03 0.405 0.07 5.18 1.05 10.71 0.334
F4 0.294 0.05 0.333 0.03 11.71 1.13 21.52 0.103
F5 0.306 0.04 0.348 0.06 12.06 1.13 24.15 0.342
F6 0.312 0.01 0.357 0.02 12.60 1.14 25.73 0.204
18.51 0.551
F7 0.319 0.05 0.348 0.05 8.33 1.09
F8 0.357 0.02 0.394 0.03 9.39 1.10 19.35 0.154
F9 0.340 0.03 0.365 0.01 6.62 1.07 15.54 0.248
* The values represent mean SD, n = 3

19. o Solubility studies of hydrochlorothiazide
and agglomerates
Formulations Solubility (mg/ml)
Hydrochlorothiazide 0.71±0.01
F0 0.73±0.24
F1 0.76±1.37
F2 0.77±1.87
F3 0.80±2.39
F4 0.78.±0.57
F5 0.82±0.34
F6 0.85±0.65
F7 0..73±2.14
F8 0.75±0.18
* The values represent mean
F9 SD, n = 3 0.78±0.41

20. Post compression
parameters
o Results for Thickness,
Hardness, Friability
Thickness* Hardness**
Formulations Friability (%)
(mm) (Kg/cm2)
F0 3.35±0.02 3.56± 0.15 0.224± 0.03
F1 3.31±0.01 4.14± 0.19 0.186±0.06
F2 3.34±0.05 4.09± 0.05 0.159±0.04
F3 3.29±0.01 4.12± 0.21 0.131±0.05
F4 3.25±0.03 4.09± 0.05 0.179±0.03
F5 3.27±0.05 3.78± 0.15 0.142±0.02
F6 3.32±0.06 4.03±0.20 0.128±0.07
F7 3.34±0.02 3.91±0.11 0.191±0.06
F8 3.31±0.08 4.01±0.09 0.167±0.03
F9 3.28±0.03 4.12 0.19 0.152 0.04
* = Average of 6 readings SD.
** = Average of 3 readings SD.

21. o Weight
variation
Formulation Weight variation(%) In vitro disintegration
time(seconds)*
F0 0.86 127
F1 0.54 114
F2 0.48 109
F3 0.32 105
F4 0.61 112
F5 0.53 106
F6 0.45 102
119
F7 0.77
F8 0.65 115
F9 0.59 110
* = Average of 6 readings SD.

22. In vitro
Dissolution
Study

23. PERCENTAGE CUMULATIVE RELEASE (%CR)
TIME (MIN)
Hydrochlorothiazide(FH)
05 15.56±1.34
15
27.66±0.45
44.65±2.75
30
62.97±2.24
45
68.91±1.89
60
Average of 3 readings SD.

24. PERCENTAGE CUMULATIVE RELEASE
(%CR)
TIME (MINUTES)
F0 (NO POLYMER)
05 11.95±0.34
15
25.68±0.25
42.57±1.25
30
57.22±3.54
45
69.76±2.84
60
Average of 3 readings SD.

25. PERCENTAGE CUMULATIVE RELEASE (%CR)
TIME (min.)
F1 F2 F3
05 14.18±2.47 15.14±1.36 16.16±2.35
15 27.88±1.58 28.84±2.54 31.10±3.12
30 48.29±2.66 45.83±1.98 51.74±1.34
45 60.49±0.84 61.12±0.51 65.60±2.25
60 71.65±0.35 73.72±0.77 75.02±0.86
Average of 3 readings SD.

26. PERCENTAGE CUMULATIVE RELEASE (%CR)
TIME (min.)
F4 F5 F6
05 16.29±0.54 17.02±1.02 17.15±0.31
15 29.57±0.96 30.05±1.23 31.45±1.09
30 47.33±2.35 48.64±2.74 49.19±1.85
45 62.47±1.12 63.17±2.55 67.19±3.52
60 74.37±3.41 76.22±1.36 78.84±2.76
Average of 3 readings SD.

27. PERCENTAGE CUMULATIVE RELEASE (%CR)
TIME (min.)
F7 F8 F9
05 12.56±0.75 9.43±3.06 7.93±1.23
15 28.16±2.31 23.76±2.54 22.77±1.85
30 44.94±2.44 43.14±0.95 40.78±0.79
45 59.75±1.75 55.91±2.85 54.95±0.81
60 71.74±1.67 67.39±1.28 66.36±2.24
Average of 3 readings SD.

28. Comparison of dissolution profiles of FH,
F0 and F6

29. CONCLUSION

30. • The present study indicates that the process of
spherical agglomeration contributed
significantly in improving the flow properties
of the drug thereby making it suitable for
direct compression. Addition of polymers was
further helpful in improving the solubility of
the drug.
• Hence it can be concluded that spherical
agglomeration is a useful tool which can be
explored in large scale to render a poorly
compressible drug suitable for direct

31. REVIEW
OF
LITERATURE

32. • Jyothikattaa et al developed spherical
agglomerates of Benzoic acid. After screening of
different methods, the influence of the amount of
the bridging liquid, the solute concentration and
the stirring rate was investigated. It was found that
favorable properties were obtained if the optimum
amount of bridging liquid was added during the
crystallization.
• Gupta et al prepared Celecoxib spherical
agglomerates with PVP using acetone, water and
chloroform as solvent, non-solvent and bridging
liquid respectively. The crystals exhibited
significantly improved micromeritic properties
compared to pure drug. The aqueous solubility and
dissolution rate of the drug from crystals were

33. • Dixit et al prepared spherical agglomerates of
Indomethacin by solvent change method.
Dissolution profile of the spherical
agglomerates was compared with commercial
and recrystallized sample. Spherical
agglomerates exhibited decreased
crystallinity and improved Micromeritic
properties.

34. THANK YOU