characterization of optimized recrystallized...

Characterization of Optimized

Recrystallized Agglomerates

Chapter 8: Characterization of optimized recrystallized agglomerates of MA

Direct tabletting and BA improvement of MA by spherical crystallization tech. 217

8. Characterization of optimized recrystallized agglomerates:

8.1. Particle shape identification by scanning electron microscopy (SEM) and

microscopical photographs:

The shape, surface characteristics and type of crystals of macrolide antibiotics and their

recrystallized agglomerates were analyzed by using a scanning electron microscopy

operating at 10 kV.The samples were dusted onto double sided tape on an aluminum stub

and sputter-coated with gold particles in an argon atmosphere.

8.1.1. SEM and microscopical photographs of ATM and recrystallized agglomerates:

Figure: 8.1. Microscopical photographs of recrystallized crystal habit of ATM in

mixture of methanol and dichloromethane.



Figure: 8.2. SEM of Azithromycin and their recrystallized agglomerates.



Figure: 8.3. Microscopical photographs of Azithromycin and Their recrystallized

agglomerates.



8.1.2. SEM and microscopical photographs of CTM and recrystallized agglomerates:

Figure: 8.4. Microscopical photographs of recrystallized crystal habit of CTM in

mixture of Ethanol and dichloromethane.



Figure:8.5. SEM photographs of CTM and CTM-Agg at different magnification.



Figure: 8.6. SEM photographs of CTM-SSG and CTM-EudS at two magification.



8.1.3. SEM and microscopical photographs of RTM and recrystallized agglomerates:

Figure: 8.7. Microscopical photographs of recrystallized crystal habit of RTM in

mixture of Ethanol and chloroform.



Figure: 8.8. SEM photographs of RTM and their recrystallized agglomerates.



8.1.4. SEM and microscopical photographs of ETM and recrystallized agglomerates:

Figure: 8.9. Microscopical photographs of recrystallized crystal habit of RTM in

mixture of Ethanol and chloroform.



Figure: 8.10. SEM photographs of ETM and their recrystallized agglomerates.



Figures 8.1, 8.4, 8.7 and 8.9 represent the microscopical photographs of crystal habit of

macrolide antibiotics ATM, CTM, RTM and ETM respectively in the mixture of good

solvent and bridging liquid. From the observations it is clears that the macrolide

antibiotics show platelets, needle or irregular stone shaped crystal habit in mixture of

good solvent and bridging liquid.

Figure: 8.2 and 8.3 represent the SEM and microscopical photographs of ATM and their

recrystallized agglomerates. Figure: 8.5 and 8.6 represent the SEM and microscopical

photographs of CTM and their recrystallized agglomerates. Figure: 8.8 represent the

SEM photographs of RTM and their recrystallized agglomerates and Figure: 8.10

represent the SEM photographs of CTM and their recrystallized agglomerates.

The micro morphological properties of the control raw crystals of macrolide antibiotics

and developed recrystallized agglomerated samples were studied by using SEM and

microscopical photographs. The above mentioned figures show a typical shape of

agglomerated and unagglomerated` crystals of macrolide antibiotics. The control

macrolide antibiotics are irregular stone shaped crystals. Their flow properties are poor

due to the crystal habit and the electrostatic charge. The spherical single particle is

formed by very small shaped recrystallized crystals, which are closely compacted into a

spherical form. In case of agglomerates obtained by QESD method, the emulsion droplets

crystallized instantaneously from their surface inward, so the resultant agglomerates were

very dense in texture. SEM with higher magnification revealed that agglomerates were

spherical aggregates of small recrystallized needle or plate shaped crystals. The bigger

particle size and the associated decreased specific surface of the agglomerates resulted in

better compactibility and cohesivity properties for the developed than the control sample.

The improvement of sphericity may be attributed to a coating developed on the

microcrystals before their binding into agglomerates, which resulted in improved

symmetry of packing and therefore sphericity of recrystallized agglomerates.



8.2 Fourier transforms infra red spectroscopy (FTIR) of macrolide antibiotics and

prepared optimized recrystallized agglomerates:

FTIR spectra of the macrolide antibiotics were recorded on Shimadzu FT IR – 8400

spectrophotometer. Potassium bromide pellet method was employed and background

spectrum was recorded under identical situation. Each spectrum was derived from single

average scans collected in the region 400 – 4000 cm-1

at spectral resolution of 2 cm-2

.

Spectra were analyzed by software supplied by Shimadzu.

8.2.1 FTIR spectra of ATM and their optimized recrystallized agglomerates.

Figure: 8.11. FTIR spectra of ATM, ATM-EudS and ATM-HEC.



Figure: 8.12. FTIR spectra of ATM-SSG, ATM-N (PEG) and ATM-HPMC.

Table: 8.1. Principal or characteristic FTIR peak of ATM and their recrystallized

agglomerates.

Sr.No Crystal code Principal peak (cm-1

)

1 ATM 1726.35 1182.40 1053.17

2 ATM-EudS 1726.35 1182.40 1053.17

3 ATM-PVP 1726.35 1182.40 1053.17

4 ATM-SSG 1726.35 1182.40 1053.17

5 ATM-N(PEG) 1720.56 1186.26 1051.24

6 ATM-HPMC 1726.35 1184.33 1053.17

Figure: 8.11 and 8.12 represent the FTIR spectra of ATM and optimized recrystallized

agglomerates.Table:8.1 represent the characteristic peaks of ATM and prepared

recrystallized agglomerates. In the range of 4000 to 500 cm-1

azithromycin exhibit a

strong sharp signal at 1726 cm-1

which is due to absorption of the carbonyl group. From

the literature survey the principal or characteristic peak of Azithromycin FTIR includes



1721, 1188, 1052cm-1

. The spectrum of recrystallized agglomerates corresponds to the

superimposition of raw crystals of azithromycin (mentioned in above table: 8.1) with no

significant shift of major peaks. The close agreement between the FT-IR spectra of the

raw azithromycin crystals and their recrystallized agglomerates suggested that there were

no changes in the ATM molecular structure caused by the recrystallization and the

agglomeration process. This confirms the presence of azithromycin in recrystallized

agglomerates without changing the chemical structure (1).

8.2.2 FTIR spectra of CTM and their optimized recrystallized agglomerates.

Figure: 8.13. FTIR spectra of CTM, CTM-EudS and CTM-PVP.



Figure: 8.14. FTIR spectra of CTM-SSG and CTM-N (HPMC).

Table: 8.2. Principal or characteristic FTIR peak of CTM and their recrystallized

agglomerates.


)

1 CTM 1732.13 1689.70 1172.76 1107.18 1051.24

2 CTM-EudS 1732.13 1689.70 1168.90 1107.18 1053.17

3 CTM-PVP 1732.13 1689.70 1172.76 1107.18 1053.17

4 CTM-SSG 1732.13 1689.70 1172.76 1107.18 1053.17

5 CTM-N(HPMC) 1732.13 1689.70 1172.76 1107.18 1053.17

Figure: 8.13 and 8.14 represent the FTIR spectra of CTM and optimized recrystallized

agglomerates.Table:8.2 represent the characteristic peaks of CTM and prepared

recrystallized agglomerates. The principal peaks of the clarithromycin includes 1734,

1692, 1108, 1170, 1052cm-1

.FT-IR spectra were measured in order to establish the

molecular state in CTM and optimized agglomerated crystals (in above mentioned

Figures).CTM crystals show characteristic peaks of C=O stretching vibration from ketone



group in a lactone ring (at 1689.17 cm−1) and from O-C=O stretching vibration in a

lactone ring (at 1732.13 cm−1). The principal peaks of clarithromycin were observed in

their recrystallized agglomerates. This indicated that there was no difference between the

internal structures and conformation of these samples at the molecular level. [2]

8.2.3 FTIR spectra of RTM and their optimized recrystallized agglomerates.

Figure: 8.15. FTIR spectra of RTM, RTM-HPC and RTM-PVP.



Figure: 8.16. FTIR spectra of RTM-SSG, RTM-N (PEG) and RTM-EudS.

Figure: 8.15 and 8.16 represent the FTIR spectra of RTM and optimized recrystallized

agglomerates.Table:8.3 represent the characteristic peaks of RTM and prepared

recrystallized agglomerates. FTIR spectrum of Roxithromycin presented characteristic

sharp peaks at

2968 cm−1 (C–H stretching vibration of alkane)

1726 cm−1 corresponding to carbonyl stretching of the lactone ring containing

more than six carbon atoms.

The presence of broad spectra at 3100 to 3710 cm−1 may be due to the presence

of bound moisture indicating incomplete drying.



Table: 8.3. Principal or characteristic FTIR peak of RTM and their recrystallized

agglomerates.


)

1 RTM 2968.55 1726.35

2 RTM-HPC 2968.55 1726.35

3 RTM-PVP 2968.55 1726.35

4 RTM-SSG 2968.55 1726.35

5 RTM-BCD 2968.55 1726.35

6 RTM-N(PEG) 2968.55 1726.35

7 RTM-EudS 2968.55 1726.35

The all above mentioned principal peaks of roxithromycin were present in their

recrystallized agglomerates (mentioned in above table: 8.3). The closeness between the

FT-IR spectra of the roxithromycin and their recrystallized agglomerates suggested that

there were no changes in the roxithromycin molecular structure due to recrystallized

agglomeration technique.

8.2.4 FTIR spectra of ETM and their optimized recrystallized agglomerates.

Figure: 8.17. FTIR spectra of ETM, ETM-EudS and ETM-BCD.



Figure: 8.18. FTIR spectra of ETM-SSG, ETM-N (PEG), ETM-PEG and ETM-F68.

Figure: 8.17 and 8.18 represent the FTIR spectra of ETM and optimized

recrystallized agglomerates.Table:8.4 represent the characteristic peaks of ETM and

prepared recrystallized agglomerates. The IR spectra of ETM and their

recrystallized agglomerates are shown in above figure. The 1715cm−1

corresponding to carbonyl stretching (C=O) of the lactone ring and 2968 cm−1 (C–

H stretching vibration of alkane) which is the principal peaks of erythromycin.



Table: 8.4. Principal or characteristic FTIR peak of ETM and their

recrystallized agglomerates.


)

1 ETM 1714.77 2972.40

2 ETM-EudS 1716.70 2972.40

3 ETM-HPMC 1716.70 2972.40

4 ETM-BCD 1716.70 2972.40

5 RTM-SSG 1716.70 2972.40

6 RTM-F68 1716.70 2972.40

7 RTM-PEG 1714.77 2972.40

8 RTM-N(PEG) 1716.70 2972.40

The result with FTIR seems to indicate there is no significant change in principal

peaks in agglomerated crystals compared to ETM.



8.3 Powder X-ray diffraction studies of macrolide antibiotics and their optimized

recrystallized agglomerates:

Powder X-ray diffraction (PXRD) patterns were traced by employing X-ray diffractometer

(Philips PW 1729, Analytical XRD, Holland) for the samples using Ni filtered CuK(α)

radiation (intensity ratio(α1/ α2): 0.500), a voltage of 40 KV, a current of 30 mA and

receiving slit of 0.2 inches. The samples were analyzed over 2 range of 5.010-39.990o

with scanning step size of 0.020 o (2 ) and scan step time of one second.

8.3.1 Powder X-ray diffraction studies of ATM and recrystallized agglomerates:

Figure:8.19. Powder X-ray diffraction studies of ATM,ATM-EudS and ATM-HEC.



Figure:8.20. Powder X-ray diffraction studies of ATM-SSG, ATM-N (PEG) and

ATM-HPMC.



Table:8.5.2θ and d-value of azithromycin and their recrystallized agglomertates.

Sr.

No.

Angle(02θ) [d-value] of ATM and their recrystallized agglomerates from XRD plot

ATM ATM-Agg ATM-EudS ATM-PVP ATM-SSG ATM-

N(PEG)

ATM-F68 ATM-BCD

1 5.065(17.44) ---------- ---------- ---------- ---------- 5.640(15.66) ---------- ----------

2 6.255(14.11) 6.135(14.40) ---------- 6.265(14.10) ---------- ---------- ---------- 6.300(14.02)

3 7.790(11.34) 7.805(11.32) 7.795(11.34) 7.965(11.10) ---------- ---------- 7.950(11.12) 7.715(11.45)

4 8.090(10.92) ---------- ---------- ---------- 8.010(11.03) 8.175(10.81) ---------- 7.985(11.07)

5 9.550(9.26) ---------- ---------- ---------- ---------- ---------- ---------- ----------

6 9.720(9.10) 9.725(9.90) 9.795(9.03) 9.755(9.06) ---------- ---------- 9.830(8.99) 9.715(9.10)

7 9.840(8.99) ---------- ---------- 9.940(8.90) 10.030(8.81) 10.140(8.72) 9.975(8.86) 9.935(8.90)

8 ---------- ---------- ---------- 11.020(8.03) ---------- ---------- ---------- ----------

9 11.285(7.84) 11.180(7.91) 11.215(7.88) 11.235(7.87) 11.355(7.79) 11.430(7.74) 11.270(7.84) 11.210(7.89)

10 11.945(7.41) ---------- ---------- ---------- ---------- ---------- 11.875(7.44) ----------

11 ---------- 12.230(7.12) 12.390(7.14) 12.275(7.21) ---------- 12.235(7.23) ---------- 12.365(7.15)

12 12.475(7.09) 12.530(7.06) 12.625(7.01) 12.785(6.92) 12.420(7.13) 12.580(7.04)

13 13.955(6.35) 13.905(6.37) 13.975(6.34) ---------- 14.070(6.29) 14.090(6.29) 14.040(6.31) 14.055(6.30)

14 14.670(6.04) 14.750(6.01) ---------- 14.110(6.28) ---------- ---------- ---------- 14.685(6.03)

15 15.325(5.78) 15.245(5.81) 15.305(5.79) 15.455(5.73) 15.455(5.73) 15.745(5.63) 15.260(5.81) 15.410(5.75)

16 15.680(5.64) ---------- ---------- ---------- ---------- ---------- ---------- ----------

17 16.205(5.46) ---------- ---------- 16.370(5.42) ---------- ---------- 16.335(5.43) ----------

18 16.510(5.37) ---------- ---------- ---------- ---------- 16.650(5.33) ---------- ----------

19 17.320(5.12) 17.130(5.18) 17.145(5.17) 17.255(5.14) 17.245(5.14) ---------- ---------- 17.180(5.16)

20 17.770(4.99) ---------- ---------- 17.710(5.01) ---------- 17.755(4.99) 17.505(5.07) 17.445(5.08)

21 18.105(4.89) ---------- ---------- ---------- ---------- ---------- ---------- ----------

22 18.550(4.78) ---------- ---------- 18.705(4.75) 18.720(4.74) 18.845(4.71) 18.750(4.73) 18.635(4.76)

23 19.045(4.66) 19.005(4.67) 19.080(4.65) 19.100(4.65) ---------- ---------- ---------- 19.050(4.66)

24 19.717(4.50) ---------- 19.860(4.46) ---------- ---------- 19.990(4.44) 19.795(4.49) 19.915(4.46)

25 20.090(4.42) 20.000(4.44) ---------- 20.000(4.44) 20.060(4.43) ---------- ---------- ----------

26 20.540(4.33) 20.410(4.35) ---------- 20.515(4.33) 20.590(4.32) ---------- 20.675(4.30) 20.495(4.33)

27 21.125(4.21) 20.930(4.25) ---------- 21.200(4.18) ---------- ---------- ---------- 21.130(4.21)

28 21.790(4.08) 21.640(4.11) ---------- ---------- ---------- 21.840(4.07) 21.670(4.09) 21.700(4.10)

29 22.365(3.98) 22.380(3.97) ---------- 22.570(3.94) ---------- ---------- 22.245(3.99) 22.415(3.97)

30 23.480(3.78) 23.415(3.80) ---------- 23.585(3.77) ---------- ---------- ---------- 23.595(3.77)

31 24.335(3.66) ---------- ---------- ---------- ---------- 24.180(3.68) 23.950(3.72) ----------

32 24.490(3.56) ---------- ---------- ---------- ---------- 25.030(3.56) 24.810(3.58) ----------

33 ---------- 25.410(3.51) 25.250(3.53) 25.620(3.48) 25.625(3.48) ---------- 25.545(3.48) 25.595(3.48)

34 26.250(3.40) ---------- ---------- ---------- ---------- 26.320(3.39) 26.100(3.42) ----------

35 ---------- ---------- ---------- ---------- ---------- ---------- 26.720(3.33) ----------

36 ---------- ---------- ---------- ---------- ---------- ---------- ---------- 27.565(3.23)

37 28.185(3.17) 28.130(3.17) ---------- ---------- ---------- 28.410(3.14) 28.200(3.17) 28.225(3.15)

38 29.225(3.06) 29.450(3.04) ---------- 29.470(3.03) ---------- ---------- 29.385(3.04) 29.545(3.02)

39 30.140(2.97) ---------- ---------- ---------- ---------- 30.625(2.92) 30.380(2.94) ----------



Table:8.5.2θ and d-value of azithromycin and their recrystallized agglomertates.

Sr.

No.

Angle(02θ) [d-value] of ATM and their recrystallized agglomerates from XRD plot

ATM ATM-Agg ATM-EudS ATM-PVP ATM- SSG ATM-

N(PEG)

ATM-F68 ATM-BCD

40 31.445(2.85) 31.575(2.83) ---------- 31.530(2.83) ---------- ---------- ---------- 31.645(2.83)

41 32.650(2.74) ---------- ---------- ---------- ---------- ---------- ---------- ----------

42 33.245(2.70) ---------- ---------- ---------- 33.655(2.66) 34.080(2.63) 33.970(2.64) 35.700(2.52)

43 36.015(2.50) 35.710(2.52) 35.705(2.51) 36.280(2.55) ---------- 36.780(2.45) ---------- ----------

44 ---------- ---------- ---------- ---------- ---------- ---------- ---------- 37.480(2.39)

45 38.565(2.33) 38.560(2.33) ---------- ---------- ---------- ---------- ---------- ----------

46 39.955(2.25) 39.655(2.28) ---------- ---------- ---------- 39.210(2.29) ---------- 40.120(2.25)

47 ---------- ---------- ---------- ---------- 41.075(2.19) 41.395(2.18) ----------

48 42.200(2.14) ---------- ---------- 42.925(2.11) ---------- 42.465(2.12) 42.985(2.10) 42.170(2.14)

49 ---------- ---------- ---------- ---------- ---------- 43.000(2.10) ---------- ----------

50 44.575(2.04) ---------- ---------- 44.480(1.99) ---------- 44.795(2.02) 44.525(2.03) ----------

51 ---------- 46.640(1.95) ---------- ---------- ---------- ---------- ---------- ----------

52 ---------- ---------- ---------- ---------- 47.050(1.93) ---------- ---------- ----------

53 ---------- ---------- ---------- ---------- ---------- ---------- 58.700(1.58) ----------

Table:8.6.Number of peaks, 2θ at highest peak and their peak count of azithromycin

and their recrystallized agglomerates

Sr.No Product Code No of

peaks

2θ at height

Peak

Peak count at

height Peak

%RDC

1 ATM 42 9.840 1076 100

2 ATM-Agg 24 9.725 380 35.32 2 ATM-EudS 11 9.795 228 21.19 3 ATM-PVP 26 9.755 433 40.24 4 ATM-SSG 13 10.030 292 27.14 5 ATM- N(PEG) 25 10.140 342 31.78 6 ATM-F68 28 9.830 538 50.00 7 ATM-BCD 30 9.715 467 43.40



8.3.2 Powder X-ray diffraction studies of CTM and recrystallized agglomerates:

Figure:8.21. Powder X-ray diffraction studies of CTM, CTM-EudS and CTM-PVP.



Figure:8.22. Powder X-ray diffraction studies of CTM-SSG and CTM-N (HPMC).



Table:8.7.2θ and d-value of Clarithromycin and their recrystallized agglomerates.

Sr.

No.

Angle(02θ) [d-value] of CTM and their recrystallized agglomerates from XRD

plot

CTM CTM-EudS CTM-PVP CTM-SSG CTM- N(HPMC)

1 8.770(10.07) 8.590(10.28) 8.610(10.27) 8.465 8.665(10.20)

2 9.180(9.63) ---------- 9.155(9.66) 8.930 ----------

3 9.695(9.12) 9.465(9.34) 9.660(9.15) 9.415 9.615(9.20)

4 10.725(8.25) ---------- ---------- 10.785 10.440(8.09)

5 10.895(8.12) 10.895(8.12) 11.050(8.01) ---------- ----------

6 11.590(7.63) ---------- 11.590(7.63) 11.350 ----------

7 11.700(7.56) ---------- ---------- ---------- 11.690(7.57)

8 12.005(7.37) ---------- 12.035(7.35) 12.235 12.275(7.15)

9 12.610(7.02) 12.325(7.18) 12.475(7.09) ---------- ----------

10 ---------- ---------- ---------- 13.635 ----------

11 13.900(6.37) 13.895(6.37) 13.890(6.38) 13.980 13.920(6.36)

12 14.300(6.19) ---------- 14.190(6.24) ---------- ----------

13 15.410(5.75) 15.140(5.85) 15.255(5.81) 15.085 15.385(5.76)

14 15.640(5.66) ---------- ---------- ---------- ----------

15 16.435(5.39) 16.330(5.43) 16.610(5.34) 16.405 ----------

16 ---------- ---------- ---------- 16.805 ----------

17 17.115(5.18) 16.910(5.24) 17.015(5.21) 17.195 17.410(5.09)

18 17.495(5.07) ---------- 17.425(5.09) 17.995 ----------

19 18.335(4.84) 18.375(4.83) 18.210(4.87) ---------- ----------

20 19.145(4.63) 19.230(4.62) 19.195(4.63) 18.930 19.220(4.62

21 20.060(4.43) ---------- 19.920(4.46) 19.765 ----------

22 20.690(4.29) 20.475(4.34) 20.605(4.31) 20.340 20.620(4.31)

23 21.475(4.14) ---------- 21.495(4.14) 21.265 ----------

24 21.715(4.09) ---------- ---------- ---------- ----------

25 22.345(3.98) 22.145(4.02) 22.335(3.98) 22.085 22.315(3.99)

26 23.285(3.82) 23.025(3.86) 23.405(3.78) 23.140 23.400(3.80)

27 24.080(3.69) ---------- 24.010(3.71) 23.945 ----------

28 25.115(3.55) 25.105(3.55) 24.945(3.57) 24.835 25.135(3.54

29 26.085(3.42) ---------- 26.025(3.43) ---------- ----------

30 26.580(3.36) 26.540(3.36) 26.630(3.35) 26.375 ----------

31 27.885(3.20) ---------- 27.865(3.20) ---------- ----------

32 28.565(3.12) ---------- 28.525(3.13) 28.370 28.370(3.15)

33 29.485(3.03) 29.950(2.98) 29.425(3.04) 29.285 ----------

34 30.350(2.95) ---------- 30.195(2.96) 30.035 ----------

35 31.530(2.84) 31.215(2.87) ---------- ---------- ----------

36 32.815(2.73) ---------- 32.790(2.73) 32.600

37 ---------- ---------- ---------- ---------- 33.190(2.70)

38 34.405(2.61) ---------- ---------- 34.945 ----------

39 35.140(2.55) ---------- 35.145(2.56) ---------- ----------

40 36.410(2.47) ---------- 36.415(2.47) 36.030 ----------



Table:8.7.2θ and d-value of Clarithromycin and their recrystallized agglomertates.

Sr.

No.

Angle(02θ) [d-value] of RTM and their recrystallized agglomerates from XRD

plot

CTM CTM-EudS CTM-PVP CTM-SSG CTM- N(HPMC)

41 37.530(2.40) 37.720(2.39) ---------- ---------- ----------

42 38.915(2.32) 38.720(2.33) 38.945(2.32) 38.745 38.865(2.32)

43 40.140(2.25) 40.035(2.26) 40.180(2.25) 40.080 40.220(2.25)

44 41.255(2.19) ---------- 41.245(2.19) ---------- ----------

45 41.825(2.16) 41.890(2.15) 41.785(2.16) 41.460 ----------

46 43.110(2.10) ---------- 42.985(2.11) 42.840 ----------

47 ---------- ---------- ---------- 44.875 ----------

48 45.590(1.99) ---------- 45.430(1.99) ---------- 45.080(2.01)

49 46.430(1.96) 46.380(1.98) ---------- 46.480 ----------

50 ---------- ---------- 54.830(1.67) ----------

Table:8.8.Number of peaks, 2θ at highest peak and their peak count and %RDC of

Clarithromycin and their recrystallized agglomerates.

Sr.No Product Code No of peaks 2θ at height

Peak

Peak count at

height Peak

%RDC

1 CTM 45 9.695 412 100

2 CTM-EudS 22 9.465 202 49.03

3 CTM-PVP 38 11.900 369 89.56

4 CTM-SSG 34 11.350 346 83.98

5 CTM- N(HPMC) 18 10.940 219 53.16



8.3.3 Powder X-ray diffraction studies of RTM and recrystallized agglomerates.

Figure:8.23. Powder X-ray diffraction studies of RTM, RTM-Agg, RTM-HPC and

RTM-PVP.



Figure:8.24. Powder X-ray diffraction studies of RTM-SSG, RTM-BCD and RTM-N

(PEG).



Table:8.9.2θ and d-value of Roxithromycin and their recrystallized agglomerates.

Sr.

No.

Angle(02θ) [d-value] of RTM and their recrystallized agglomerates from XRD plot

RTM RTM

-Agg

RTM-

PVP

RTM-

N(PEG)

RTM-

HPC

RTM-

EudS

RTM-

BCD

1 5.530(15.97) ---------- ---------- ----------

2 7.290(12.11) ---------- ---------- ---------- ---------- ---------- ----------

3 7.925(11.14) ---------- ---------- ---------- ---------- ---------- ----------

4 8.320(10.62) 8.260(10.69) 8.575(10.30) 8.430(8.430) 8.515(10.37) 8.290(10.66) 8.250(10.71)

5 9.020(9.80) 9.825(8.99) ---------- ---------- ---------- 9.785(9.03) 9.705(9.11)

6 9.820(8.99) 9.980(8.85) ---------- ---------- 9.995(8.85) 9.920(8.91) ----------

7 10.895(8.11) 10.875(8.13) 10.010(8.83) 10.010(8.83) ---------- ---------- ----------

8 11.450(7.72) 11.635(7.59) 11.125(7.95) ---------- 11.150(7.93) 10.955(8.07) 10.955(8.07)

9 11.675(7.57) 11.855(7.46) 11.860(7.46) 11.850(7.47) 11.870(7.45) 11.750(7.54) 11.560(7.65)

10 12.105(7.31) ---------- ---------- ---------- ---------- ---------- ----------

11 12.365(7.15) ---------- ---------- ---------- ---------- ---------- ----------

12 13.025(6.79) 13.180(6.71) 13.245(6.67) ---------- ---------- 13.165(6.72) ----------

13 13.270(6.66) ---------- 13.455(6.57) 13.430(6.59) 13.450(6.58) 13.335(6.66) 13.215(6.70)

14 14.035(6.30) ---------- ---------- ---------- ---------- 14.195(6.23) 14.170(6.25)

15 14.475(6.11) 14.225(6.22) 14.450(6.13) ---------- 14.365(6.17) ---------- ----------

16 14.670(6.03) 14.685(6.03) ---------- 14.510(6.10) ---------- 14.585(6.07) 14.610(6.06)

17 16.045(5.52) 16.025(5.53) 16.030(5.53) 16.185(5.48) 16.195(5.47) 16.005(5.54) 15.875(5.58)

18 16.680(5.31) 16.845(5.26) 16.970(5.23) 16.950(5.23) 16.935(5.23) 16.790(5.28) 16.700(5.31)

19 17.320(5.12) 17.375(5.09) 17.495(5.07) ---------- 17.490(5.07) 17.255(5.14) 17.155(5.17)

20 17.770(4.99) 17.725(4.99) 17.900(4.95) 17.580(5.04) 17.905(4.95) 17.725(4.99) 17.725(4.99)

21 18.280(4.85) ---------- ---------- 18.010(4.92) ---------- ---------- ----------

22 18.825(4.71) 18.815(4.71) 18.905(4.69) ---------- 18.995(4.67) 18.775(4.72) 18.705(4.75)

23 19.335(4.58) ---------- ---------- 19.425(4.57) ---------- ---------- ----------

24 19.715(4.49) ---------- ---------- ---------- ---------- ---------- ----------

25 20.465(4.34) ---------- 20.685(4.29) ---------- 20.585(4.31) 20.445(4.34) 20.395(4.35)

26 21.245(4.18) ---------- 21.205(4.19) ---------- 21.175(4.20) 21.095(4.21) 20.905(4.25)

27 21.645(4.10) ---------- 21.880(4.06) 21.920(4.05) 21.865(4.07) 21.760(4.08) 21.605(4.11)

28 22.035(4.03) 22.090(4.02) ---------- ---------- ---------- 22.125(4.01) 22.050(4.03)

29 22.395(3.97) ---------- 22.320(3.98) 22.435(3.96) 22.345(3.98) ---------- ----------

30 23.445(3.80) 23.035(3.85) 23.110(3.85) 23.155(3.84) 23.145(3.84) 22.950(3.88) 22.865(3.89)

31 24.225(3.67) 24.445(3.64) 24.405(3.65) ---------- 24.495(3.64) 24.300(3.66) 24.340(3.66)

32 25.220(3.53) 25.455(3.50) 25.505(3.49) ---------- 25.505(3.49) 25.380(3.51) 25.370(3.51)

33 25.995(3.43) ---------- ---------- ---------- ---------- ---------- ----------

34 26.705(3.34) 26.080(3.41) 26.205(3.40) ---------- 26.055(3.42) 26.010(3.43) 26.000(3.43)

35 27.285(3.27) 27.095(3.28) 27.100(3.29) ---------- ---------- ---------- ----------

36 27.765(3.21) ---------- ---------- ---------- ---------- ---------- ----------

37 28.085(3.17) 28.130(3.17) 28.305(3.16) 28.290(3.15) 28.220(3.16) 28.060(3.18) 28.100(3.18)



Table:8.9.2θ and d-value of Roxithromycin and their recrystallized agglomerates.

Sr.N

o.

Angle(02θ) [d-value] of RTM and their recrystallized agglomerates from XRD plot

RTM RTM

-Agg

RTM-PVP RTM-N(PEG) RTM-HPC RTM-EudS RTM-BCD

38 28.735(3.10) ---------- ---------- ---------- ---------- ----------

39 29.275(3.05) 29.860(2.98) 29.950(2.98) ---------- 30.015(2.98) 29.785(2.99) 29.855(2.99)

40 31.080(2.87) 31.085(2.87) 31.185(2.87) 31.250(2.86) 31.215(2.87) 31.090(2.88) 31.015(2.88)

41 32.075(2.78) ---------- ---------- ---------- ---------- ---------- ----------

42 33.145(2.70) 33.095(2.70) 33.205(2.70) ---------- 33.225(2.70) 33.145(2.70) 33.010(2.72)

43 33.655(2.66) ---------- ---------- ---------- ---------- 33.770(2.66) ----------

44 34.945(2.57) 34.360(2.61) 34.665(2.59) ---------- ---------- ---------- ----------

45 35.835(2.50) 35.590(2.52) 35.760(2.51) ---------- ---------- 35.700(2.52) ----------

46 36.830(2.43) ---------- ---------- ---------- ---------- ---------- ----------

47 38.085(2.36) 38.105(2.36) 38.100(2.37) ---------- 38.080(2.36) 37.960(2.37) 37.850(2.38)

48 39.020(2.30) ---------- ---------- ---------- ---------- ---------- ----------

49 40.230(2.24) 40.215(2.24) 40.315(2.24) 40.400(2.24) 40.210(2.24) 40.420(2.23) 40.175(2.24)

50 40.720(2.21) ---------- ---------- ---------- ---------- ---------- ----------

51 41.285(2.19) ---------- ---------- ---------- ---------- ---------- ----------

52 42.015(2.14) ---------- ---------- ---------- ---------- ---------- ----------

53 43.005(2.10) 43.205(2.09) 43.380(2.09) ---------- 43.285(2.09) 43.395(2.09) 43.175(2.09)

54 45.805(1.97) ---------- ---------- ---------- ---------- ---------- 45.620(1.99)

55 46.710(1.94) 46.770(1.94) 46.890(1.94) ---------- ---------- ---------- ----------

56 49.820(1.82) 50.855(1.79) 48.430(1.88) ---------- ---------- ---------- ----------

57 53.065(1.72) ---------- 54.820(1.68) ---------- ---------- 53.405(1.72) ----------

58 56.325(1.63) ---------- ---------- ---------- ---------- ---------- ----------

59 57.745(1.59) ---------- 57.820(1.60) 57.825(1.60) ---------- ---------- ----------

60 59.180(1.55) ---------- ---------- ---------- ---------- ---------- ----------

Table:8.10.No of peaks, 2θ at highest peak and their peak count and %RDC of

Roxithromycin and their recrystallized agglomerates.

Sr.No Product Code No of peaks 2θ at height

Peak

Peak count at

height Peak

%RDC

1 RTM 59 14.475 1399 100

2 RTM-Agg 32 9.825 562 40.17

3 RTM-PVP 35 10.010 581 41.53

4 RTM-N(PEG) 18 10.010 259 18.51

5 RTM-HPC 26 9.995 595 42.53

6 RTM-EudS 32 9.785 433 30.95

7 RTM-BCD 28 9.705 502 35.88



8.3.4 Powder X-ray diffraction studies of ETM and recrystallized agglomerates.

Figure:8.25. Powder X-ray diffraction studies of ETM, ETM-EudS and ETM-BCD.



Figure:8.26. Powder X-ray diffraction studies of ETM-HPMC and ETM-SSG.



Table:8.11.2θ and d-value of Erythromycin and their recrystallized agglomerates.

Sr.

No.

Angle(02θ) [d-value] of ETM and their recrystallized agglomerates from XRD plot

ETM ETM

-Agg

ETM-

HPC

ETM-

EudS

ETM-

N(HPMC)

ETM-

BCD

ETM-

SSG

1 7.400(11.94) 7.175(12.31) ---------- ---------- ---------- 7.490(11.80) ----------

2 9.245(9.56) 9.175(9.63) 9.120(9.69) 9.250(9.55) 9.210(9.59) ---------- ----------

3 9.685(9.13) ---------- ---------- ---------- ---------- 9.730(9.08) 9.705(9.11)

4 10.175(8.69) 10.100(8.75) ---------- ---------- ---------- ---------- 10.150(8.71)

5 10.330(8.55) ---------- ---------- ---------- 10.340(8.55) 10.360(8.53) ----------

6 12.025(7.36) ---------- ---------- ---------- ---------- 12.140(7.28) 11.955(7.44)

7 12.980(6.81) 12.900(6.86) 12.535(7.06) 12.790(6.92) ---------- ---------- 12.955(6.83)

8 13.710(6.45) ---------- ---------- ---------- 13.005(6.81) 13.125(6.74) ----------

9 14.365(6.16) 14.205(6.23) ---------- ---------- 14.450(6.13) 14.485(6.11) 14.270(6.20)

10 ---------- ---------- 15.215(5.82) ---------- 15.330(5.77) 15.440(5.74) ----------

11 16.190(5.47) ---------- ---------- ---------- 16.150(5.48) 16.630(5.42) 16.180(5.47)

12 17.300(5.12) 17.265(5.14) ---------- ---------- ---------- 17.410(5.09) 17.305(5.12)

13 17.795(4.98) ---------- ---------- ---------- 17.555(5.05) ---------- ----------

14 19.195(4.62) 19.145(4.64) 19.065(4.65) 19.125(4.64) 19.180(4.62) 19.270(4.61) 19.125(4.64)

15 20.085(4.41) 19.855(4.46) ---------- ---------- ---------- 20.020(4.43) 19.925(4.45)

16 20.790(4.26) ---------- ---------- ---------- 20.980(4.24) 20.805(4.27) 20.765(4.27)

17 21.410(4.15) ---------- ---------- ---------- ---------- 21.495(4.13) 21.370(4.15)

18 22.070(4.03) ---------- ---------- ---------- ---------- 22.120(4.02) ----------

19 22.795(3.89) ---------- ---------- ---------- ---------- 22.685(3.92) 22.510(3.95)

20 23.350(3.81) ---------- ---------- ---------- ---------- 23.370(3.81) 23.210(3.83)

21 23.635(3.76) ---------- ---------- ---------- ---------- ---------- ----------

22 26.185(3.40) ---------- ---------- ---------- ---------- 26.220(3.40) ----------

23 26.995(3.30) ---------- ---------- ---------- ---------- 26.965(3.31) 26.830(3.32)

24 27.820(3.20) ---------- ---------- ---------- ---------- 28.020(3.18) 27.850(3.20)

25 29.590(3.02) 29.610(3.02) ---------- ---------- 29.815(2.99) 29.650(3.01) 29.600(3.02)

26 30.805(2.91) ---------- ---------- ---------- ---------- 30.785(2.90) 30.620(2.92)

27 34.095(2.63) ---------- ---------- ---------- ---------- 34.065(2.62) ----------

28 ---------- ---------- ---------- ---------- ---------- 34.955(2.57) ----------

29 ---------- ---------- ---------- ---------- ---------- 37.200(2.42) 37.005(2.43)

30 ---------- ---------- ---------- ---------- ---------- 41.040(2.20) ----------

31 44.650(2.59) ---------- ---------- ---------- ---------- ---------- ----------

32 45.870(2.51) ---------- ---------- ---------- ---------- ---------- ----------

33 47.230(2.41) ---------- ---------- ---------- ---------- ---------- ----------

34 49.470(2.28) ---------- ---------- ---------- ---------- 50.565(1.80) 50.210(1.82)

35 54.105(2.06) ---------- ---------- ---------- ---------- ---------- ----------

36 55.650(1.65) ---------- ---------- ---------- ---------- ---------- ----------



Table:8.12.No of peaks, 2θ at highest peak and their peak count and %RDC of

Erythromycin and their recrystallized agglomerates. Sr.No Product Code No of peaks 2θ at height

Peak

Peak count at

height Peak

%RDC

1 ETM 32 12.980 467 100

2 ETM-Agg 9 10.100 79 16.92

3 ETM-HPC 4 9.120 50 10.71

4 ETM-EudS 3 9.250 49 10.49

5 ETM- N(HPMC) 10 9.210 106 22.70

6 ETM-BCD 26 13.125 331 70.88

7 ETM-SSG 19 10.150 188 40.26

Figures 8.19, 8.20 and tables 8.5 and 8.6 represent the XRPD spectra and data of ATM and

recrystallized agglomerates. Figure: 8.21, 8.22 and table: 8.7 and 8.8 represent the XRPD

spectra and data of CTM and recrystallized agglomerates. Figure: 8.23, 8.24 and table:

8.9and 8.10 represent the XRPD spectra and data of RTM and recrystallized agglomerates.

Figure: 8.25, 8.26 and table: 8.11and 8.12 represent the XRPD spectra and data of ETM

and recrystallized agglomerates.

X-ray diffraction pattern for macrolide antibiotics indicated a crystalline form. A sharp

peak between 9–150 2θ was characteristic of the raw crystals of the macrolide antibiotics.

The lack of sharp peaks for macrolide antibiotics was observed in recrystallized

agglomerates indicating transition of crystalline to an amorphous state. Recrystallized

agglomerates had shown peak with reduced intensities indicating decrease in the drug

crystallinity.

The maximum disappearances of peaks were observed in the recrystallized agglomerated

crystals of macrolide antibiotics. There is difference in d-spacing between the XRD spectra

of macrolide antibiotics and the agglomerated crystals at respective 2θ angle referring the

habit modification and change in the intensity of peaks, which indicate different

arrangement of the molecules hence confirming the development of different polymorphic

form.

According to the obtained X-ray diffraction pattern macrolide antibiotics show large

number of peaks and having larger peak counts at highest intense peak comparative to

recrystallized agglomerates. A few diffuse peaks or decrease in crystallinity were observed

in the some agglomerated crystals with different polymers used which may indicate slight

physical interaction of drug with polymers. The decreased drug crystallite size can explain

the faster dissolution rate of the recrystallized agglomerated samples.

The relative degree of crystallinity (RDC) was calculated by ratio of peak intensity of pure

macrolide antibiotic and recrystallized agglomerates. The % relative degree of crystallinity

(% RDC) is reported in tables 8.6, 8.8, 8.10, and 8.12 for ATM, CTM, RTM, ETM and

their respective recrystallized agglomerated crystals. There is significance reduction in

number of peaks, peak intensity and %RDC in prepared recrystallized agglomerates

compared to raw crystals of macrolide antibiotics. The PXRD studies revealed the

substantial loss of crystallinity in recrystallized agglomerates than that of pure macrolide

antibiotics.



8.4 Differential scanning calorimetric (DSC) studies of macrolide antibiotics and

recrystallized agglomerates:

Differential scanning calorimetric (DSC) analyses of the samples were carried out by using

differential scanning calorimeter equipped with computer analyzer (Shimadzu TA –60

differential scanning calorimeter, Shimadzu Corporation, Kyoto, Japan). Samples (of 3-7

mg) were heated under nitrogen atmosphere on an aluminum pan at a heating rate of 10

°C/min over the temperature range of 20-3500C.

8.4.1 DSC studies of ATM and their recrystallized agglomerates:

Azithromycin (ATM):

Figure:8.27. DSC spectra of Azithromycin (ATM).



Figure:8.28. DSC spectra of ATM-SSG and ATM-EudS.

Figure: 8.27 and 8.28 represent the DSC spectra of ATM and their recrystallized

agglomerates ATM-SSG and ATM-EudS. The azithromycin DSC curve shows sharp

endothermic peak at 108.250C indicating its melting point. The optimized recrystallized

agglomerates with sodium starch glycolate (ATM-SSG) and Eudragit S100 (ATM-EudS)

show endothermic peaks at 82.120C and 95.19

0C respectively. This indicated that

decrease in melting point due to conversion of polymorphic form and crystal habit.



8.4.2 DSC studies of CTM and their recrystallized agglomerates:

Figure:8.29. DSC spectra of CTM, CTM-PVP and CTM-SSG.



Figure: 8.29 represent the DSC spectra of CTM and their recrystallized agglomerates

CTM-PVP and CTM-SSG.The DSC study revealed endothermic peak at 220o – 230

oC for

clarithromycin (CTM) at 0oC to 400

oC. The sharp endothermic peak for CTM was

observed as 228.110C indicating its melting point. The observed endothermic peak for

CTM-PVP and CTM-SSG are 228.68 and 228.65 respectively. Which indicate there is

insignificant difference in endothermic peak of CTM and their recrystallized

agglomerates with PVP and SSG.

8.4.3 DSC studies of RTM and their recrystallized agglomerates:

Figure:8.30. DSC spectra of RTM, CTM-HPC and RTM-SSG.



Figure: 8.30 show an endothermic peak at 130.41 °C for RTM, which can be attributed to

the melting of Roxithromycin. The optimized recrystallized agglomerates show decrease

in melting point 123.020C (RTM-HPC) and 122.45

0C (RTM-SSG) which indicate slight

transformation of roxithromycin to amorphous form and decrease in melting point. The

decrease in melting point may be also due to incorporation of the drug in softened

polymer during the DSC run. The conversion of crystalline solid into partially amorphous

solid surfaces leads to a “dynamic nature “of the recrystallized agglomerates. The

presence of a broad peak may be due to partial conversion to amorphous form and also

lowering of melting point is observed due to melting point depression with shift of the

peak.

Drastic reduction in the energy may be attributed to the conversion to the amorphous

form and its interaction with the polymers. Thus, it can be concluded that complete loss

of crystallinity was observed in case of recrystallized agglomerates. These results proved

the applicability of spherical crystallization to synergistically enhance the efficacy of

processing technology with the aqueous system.



8.4.4 DSC studies of ETM and their recrystallized agglomerates.

Figure:8.31. DSC spectra of ETM, ETM-EudS and ETM-N (HPMC).



The Erythromycin base used was dehydrating showed dehydration peak in DSC curves

(figure: 8.31) at 89.510C. Liquefaction peak appeared at 142.34°C. After melting,

erythromycin dehydrated dihydrate transformed into erythromycin anhydrate which is

another erythromycin crystal form. Its melting point peak appears at approximately

196.30°C.The prepared recrystallized agglomerates ETM-EudS and ETM-N (HPMC)

show change in dehydration peak at 73.600C and 96.32

0C respectively. There is also

change in liquefaction peak for ETM-EudS and ETM-N (HPMC) at 132.680C and

157.110C and finally also reduces the melting endothermic peak for ETM-EudS at

173.580C and disappeared for ETM-N (HPMC).These changes in the endothermic peaks

might be due to changes in the internal structure or crystal form of the erythromycin base

[4] .

8.5. References:

1. Gandhi R, Pillai O, Thilagavathi R, Gopalakrishnan B, Lal Kaula C,

Panchagnulaa R (2002) Characterization of Azithromycin hydrates. Eur. J.

Pharm. Sci. 16; 175–184.

2. Inoue Y, Yoshimura S, Tozuka Y, Moribe K, Kumamoto T, Ishikawa T,

Yamamoto K (2007) Application of ascorbic acid 2-glucoside as a solubilizing

agent for clarithromycin: Solubilization and nanoparticle formation. Int. J. Pharm.

331 38–45.

3. Biradar SV, Patil AR, Sudarsan GV, Pokharkar VB (2006) A comparative study

of approaches used to improve solubility of roxithromycin. Powder Technology.

169; 22–32.

4. Wang Z, Wang J, and Dang L (2006) Thermal, phase transition and spectral

studies in erythromycin pseudo polymorphs: dihydrate and acetone solvate. Cryst.

Res. Technol. 41(12); 1219–1225.

characterization of optimized recrystallized...

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